Non-invasive treatment of bronchial constriction

ABSTRACT

Devices, systems and methods are disclosed for treating bronchial constriction related to asthma, anaphylaxis or chronic obstructive pulmonary disease. The treatment comprises transmitting impulses of energy non-invasively to selected nerve fibers that are responsible for smooth muscle dilation. The transmitted energy impulses, comprising magnetic and/or electrical, mechanical and/or acoustic, and optical and/or thermal energy, stimulate the selected nerve fibers.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Nonprovisional application Ser.No. 12/859,568 filed 19 Aug. 2010; which is incorporated herein byreference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes, andmore specifically to non-invasive devices and methods for treatingconditions associated with bronchial constriction. The energy impulses(and/or fields) comprise electrical and/or magnetic, mechanical and/oracoustic, and optical and/or thermal energy.

There are a number of treatments for various infirmities that requirethe destruction of otherwise healthy tissue in order to affect abeneficial effect. Malfunctioning tissue is identified, and thenlesioned or otherwise compromised in order to affect a beneficialoutcome, rather than attempting to repair the tissue to its normalfunctionality. While there are a variety of different techniques andmechanisms that have been designed to focus lesioning directly onto thetarget nerve tissue, collateral damage is usually inevitable.

Still other treatments for malfunctioning tissue can be medicinal innature, in many cases leaving patients to become dependent uponartificially synthesized chemicals. Examples of this are anti-asthmadrugs such as albuterol, proton pump inhibitors such as omeprazole(Prilosec), spastic bladder relievers such as Ditropan, and cholesterolreducing drugs like Lipitor and Zocor. In many cases, these medicinalapproaches have side effects that are either unknown or quitesignificant. For example, at least one popular diet pill of the late1990's was subsequently found to cause heart attacks and strokes.Unfortunately, the beneficial outcomes of surgery and medicines are,therefore, often realized at the cost of function of other tissues, orrisks of side effects.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue, which stimulation is generally a whollyreversible and non-destructive treatment, holds significant promise forthe treatment of many ailments.

Electrical stimulation of the brain with implanted electrodes has beenapproved for use in the treatment of various conditions, including painand movement disorders including essential tremor and Parkinson'sdisease. The principle behind these approaches involves disruption andmodulation of hyperactive neuronal circuit transmission at specificsites in the brain. As compared with the very dangerous lesioningprocedures in which the portions of the brain that are behavingpathologically are physically destroyed, electrical stimulation isachieved by implanting electrodes at these sites to, first senseaberrant electrical signals and then to send electrical pulses tolocally disrupt the pathological neuronal transmission, driving it backinto the normal range of activity. These electrical stimulationprocedures, while invasive, are generally conducted with the patientconscious and a participant in the surgery.

Brain stimulation, and deep brain stimulation in particular, is notwithout some drawbacks. The procedure usually requires penetrating theskull, and inserting an electrode into the brain matter using acatheter-shaped lead, or the like. While monitoring the patient'scondition (such as tremor activity, etc.), the position of the electrodeis adjusted to achieve significant therapeutic potential. Next,adjustments are made to the electrical stimulus signals, such asfrequency, periodicity, voltage, current, etc., again to achievetherapeutic results. The electrode is then permanently implanted andwires are directed from the electrode to the site of a surgicallyimplanted pacemaker. The pacemaker provides the electrical stimulussignals to the electrode to maintain the therapeutic effect. While thetherapeutic results of deep brain stimulation are promising, there aresignificant complications that arise from the implantation procedure,including stroke induced by damage to surrounding tissues and theneurovasculature.

One of the most successful modern applications of this basicunderstanding of the relationship between muscle and nerves is thecardiac pacemaker. Although its roots extend back into the 1800's, itwas not until 1950 that the first practical, albeit external and bulkypacemaker was developed. Dr. Rune Elqvist developed the first trulyfunctional, wearable pacemaker in 1957. Shortly thereafter, in 1960, thefirst fully implanted pacemaker was developed.

Around this time, it was also found that the electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to Deno, et al., the disclosure of which is incorporatedherein by reference).

Another application of electrical stimulation of nerves has been thetreatment of radiating pain in the lower extremities by means ofstimulation of the sacral nerve roots at the bottom of the spinal cord(see U.S. Pat. No. 6,871,099 to Whitehurst, et al., the disclosure ofwhich is incorporated herein by reference).

Nerve stimulation is thought to be accomplished directly or indirectlyby depolarizing a nerve membrane, causing the discharge of an actionpotential; or by hyperpolarization of a nerve membrane, preventing thedischarge of an action potential. Such stimulation may occur afterelectrical energy, or also other forms of energy, are transmitted to thevicinity of a nerve [F. RATTAY. The basic mechanism for the electricalstimulation of the nervous system. Neuroscience Vol. 89, No. 2, pp.335-346, 1999; Thomas HEIMBURG and Andrew D. Jackson. On solitonpropagation in biomembranes and nerves. PNAS vol. 102 (no. 28, Jul. 12,2005): 9790-9795]. Nerve stimulation may be measured directly as anincrease, decrease, or modulation of the activity of nerve fibers, or itmay be inferred from the physiological effects that follow thetransmission of energy to the nerve fibers.

The present disclosure involves medical procedures that stimulate nervesby non-invasively transmitting different forms of energy to nerves. Amedical procedure is defined as being non-invasive when no break in theskin (or other surface of the body, such as a wound bed) is createdthrough use of the method, and when there is no contact with an internalbody cavity beyond a body orifice (e.g, beyond the mouth or beyond theexternal auditory meatus of the ear). Such non-invasive procedures aredistinguished from invasive procedures (including minimally invasiveprocedures) in that the invasive procedures insert a substance or deviceinto or through the skin (or other surface of the body, such as a woundbed) or into an internal body cavity beyond a body orifice. Thefollowing paragraphs give examples of non-invasive medical procedures,contrasting some of them with corresponding invasive medical procedures.

For example, transcutaneous electrical stimulation of a nerve isnon-invasive because it involves attaching electrodes to the surface ofthe skin (or using a form-fitting conductive garment) without breakingthe skin. In contrast, percutaneous electrical stimulation of a nerve isminimally invasive because it involves the introduction of an electrodeunder the skin, via needle-puncture of the skin.

Another form of non-invasive electrical stimulation, known as magneticstimulation, involves the generation (induction) of an eddy currentwithin tissue, which results from an externally applied time-varyingmagnetic field. The principle of operation of magnetic stimulation,along with a list of medical applications of magnetic stimulation, isdescribed in: Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006. As described in thatGuide, applications of magnetic stimulation include the stimulation ofselected peripheral nerves, as well as stimulation of selected portionsof the brain (transcranial magnetic stimulation). Mechanisms underlyingbiological effects that result from applying such time-varying magneticfields are reviewed in: PILLA, A. A. Mechanisms and therapeuticapplications of time varying and static magnetic fields. In Barnes F andGreenebaum B (eds), Biological and Medical Aspects of ElectromagneticFields. Boca Raton Fla.: CRC Press, 351-411 (2006).

Diathermy includes non-invasive methods for the heating of tissue, inwhich the temperature of tissues is raised by high frequency current,ultrasonic waves, or microwave radiation originating outside the body.With shortwave, microwave and radiofrequency diathermy, the tissue to betreated is irradiated with electromagnetic fields having a carrierfrequency of typically 13.56, 27.12, 40.68, 915 or 2450 MHz, modulatedat frequencies of typically 1 to 7000 Hz. The heating effects may bedielectric, wherein molecules in tissues try to align themselves withthe rapidly changing electric field, and/or induced, wherein rapidlyreversing magnetic fields induce circulating electric currents andelectric fields in the body tissues, thereby generating heat. Withultrasound diathermy, high-frequency acoustic vibrations typically inthe range of 800 to 1,000 KHz are used to generate heat in deep tissue.

Devices similar to those used with diathermy deliver electromagneticwaves non-invasively to the body for therapeutic purposes, withoutexplicitly intending to heat tissue. For example, U.S. Pat. No.4,621,642, entitled Microwave apparatus for physiotherapeutic treatmentof human and animal bodies, to Chen, describes apparatus for performingacupuncture treatment with microwaves. U.S. Pat. No. 5,131,409, entitledDevice for microwave resonance therapy, to Lobarev et al. discloses thetransmission of an electromagnetic wave that is propagated along aslotted transmission line in free space toward the patient's skin, forapplications analogous to laser acupuncture. U.S. Pat. No. 7,548,779,entitled Microwave energy head therapy, to Konchitsky, discloses thetransmission of high frequency electromagnetic pulses non-invasively toa patient's head, for purposes of treating headaches, epilepsy, anddepression, wherein the brain behaves as an antenna for receivingelectromagnetic energy at certain wavelengths.

Acupuncture (meridian therapy) may be non-invasive if the acupuncturetool does not penetrate the skin, as practiced in Toyohari acupunctureand the pediatric acupuncture style Shonishin. Other forms ofacupuncture may also be non-invasive when they use the Teishein, whichis one of the acupuncture needles described in classical texts ofacupuncture. Even though it is described as an acupuncture needle, theTeishein does not pierce or puncture the skin. It is used to apply rapidpercussion pressure to the meridian point being treated, so its use mayalso be described as a form of acupressure. Electroacupuncture is oftenperformed as a non-invasive transcutaneous form of electrostimulation.Laser acupuncture and colorpuncture are also non-invasive in thatacupuncture meridian points are stimulated at the surface of the skinwith light, rather than mechanically or electrically. Although it ispossible to compare the effectiveness of acupuncture treatment with theeffectiveness of Western types of treatments for recognized disorderssuch as asthma, it is always possible to ascribe any differences ineffectiveness to differences in mechanisms. This is because acupuncturetreats patients by stimulating acupuncture meridian points, not tissuesuch as nerves or blood vessels as identified by modern westernmedicine. Furthermore, acupuncture endeavors to produce effects that arenot contemplated by modern western medicine, such as the de qisensation, and results using acupuncture may be confounded by theindividualized selection of meridian points, as well as by thesimultaneous treatment with herbal medicines. For example, acupunctureis not considered to be effective for the treatment of asthma [McCARNEYR W, Brinkhaus B, Lasserson T J, Linde K. Acupuncture for chronic asthma(Review). The Cochrane Library 2009, Issue 3. John Wiley & Sons, Ltd.;Michael Y. SHAPIRA, Neville Berkman, Gila Ben-David, Avraham Avital,Elat Bardach and Raphael Breuer. Short-term Acupuncture Therapy Is of NoBenefit in Patients With Moderate Persistent Asthma. CHEST 2002;121:1396-1400; W GRUBER, E Eber, D Malle-Scheid, A Pfleger, E Weinhandl,L Dorfer, M S Zach. Laser acupuncture in children and adolescents withexercise induced asthma. Thorax 2002; 57:222-225], but even if were tohave been shown effective, such effectiveness would, by definition, beattributable only to the stimulation of meridian points, as interpretedin terms of theories related to oriental medicine (e.g., restoration ofQi balance in Traditional Chinese Medicine).

Other forms of non-invasive medical procedures direct mechanicalvibrations to selected organs or are used to massage muscles. Forexample, mechanical vibrations applied to the chest are used byphysiotherapists to dislodge mucus in the lungs. [M. J. GOODWIN.Mechanical chest stimulation as a physiotherapy aid. Med. Eng. Phys.,1994, Vol. 16, 267-272; Harriet SHANNON, Rachael Gregson, Janet Stocks,Tim J. Cole, Eleanor Main. Repeatability of physiotherapy chest wallvibrations applied spontaneously breathing adults. Physiotherapy 95(2009) 36-42; McCARREN B, Alison J A and Herbert R D (2006): Vibrationand its effect on the respiratory system. Australian Journal ofPhysiotherapy 52: 39-43]. It is believed that such vibration stimulatesthe skeletal muscles involved in breathing, although vibration at 100,105, or 120 Hz might also potentially excite intrapulminary receptors[A. P. BINKS, E. Bloch-Salisbury, R. B. Banzett, R. M. Schwartzstein.Oscillation of the lung by chest-wall vibration. Respiration Physiology126 (2001) 245-249; Ikuo HOMMA. Inspiratory inhibitory reflex caused bythe chest wall vibration in man. Respiration Physiology (1980) 39,345-353]. Similarly, non-invasive mechanical ventilators use a facemask, an upper body shell known as a cuirass, or a Hayek Oscillator toforce air in and out of the lungs, thereby avoiding the use of aninvasive endotracheal tube.

The mechanical larynx is another example of a non-invasive mechanicaldevice, which is placed under the mandible so as to produce vibrationsthat the patient uses to create speech. Similarly, a hearing aid directsmechanical vibrations (acoustical or sound vibrations) to the eardrum.Because it is placed in a natural orifice (the ear canal or externalauditory meatus), the hearing aid is considered to be non-invasive.Extracorporeal shock wave lithotripsy is another non-invasive mechanicaltreatment, which is used to break-up kidney stones by focusing onto thestones a high-intensity acoustic pulse that originates from outside thebody.

Imaging procedures that require the insertion of an endoscope or similardevice through the skin or into a cavity beyond a natural orifice (e.g.,bronchoscopy or colonoscopy) are invasive. But capsule endoscopy, inwhich a camera having the size and shape of a pill is swallowed, isnon-invasive because the capsule endoscope is swallowed rather thaninserted into a body cavity. Such a swallowed capsule could also be usedto perform non-invasive stimulation of tissue in its vicinity fromwithin the digestive tract. Similarly, administration of a drug orbiologic through a transdermal patch is non-invasive, whereasadministration of a drug or biologic through a hypodermic needle isinvasive. The acts of taking a drug or biologic orally or throughinhalation are not considered to be medical procedures in the strictsense (so the issue of invasiveness does not arise), because those actsare functionally indistinguishable from the normal acts of eating,drinking, or breathing substances that may be metabolized or otherwisedisposed of by the body.

Radiological procedures, such as X-ray imaging (fluoroscopy), magneticresonance imaging and ultrasound imaging, are non-invasive unless atransducer is inserted into a body cavity or under the skin (e.g., whenan ultrasound transducer is inserted into the patient's esophagus).However, a non-invasive radiological procedure may be a component of alarger procedure having invasive components. For example, a component ofthe procedure is invasive when the formation of an image or delivery ofenergy relies on the presence of a contrast agent, enhancer,tissue-specific label or radioactive emitter that is inserted into thepatient with a hypodermic needle.

In the present application, the non-invasive delivery of energy isintended ultimately to dilate bronchial passages, by relaxing bronchialsmooth muscle. The smooth muscles that line the bronchial passages arecontrolled by a confluence of vagus and sympathetic nerve fiberplexuses. Spasms of the bronchi during asthma attacks and anaphylacticshock can often be directly related to pathological signaling withinthese plexuses. Anaphylactic shock and asthma are major health concerns.

Asthma, and other airway occluding disorders resulting from inflammatoryresponses and inflammation-mediated bronchoconstriction, affects anestimated eight to thirteen million adults and children in the UnitedStates. A significant subclass of asthmatics suffers from severe asthma.An estimated 5,000 persons die every year in the United States as aresult of asthma attacks. Up to twenty percent of the populations ofsome countries are affected by asthma, estimated at more than a hundredmillion people worldwide. Asthma's associated morbidity and mortalityare rising in most countries despite increasing use of anti-asthmadrugs.

Asthma is characterized as a chronic inflammatory condition of theairways. Typical symptoms are coughing, wheezing, tightness of the chestand shortness of breath. Asthma is a result of increased sensitivity toforeign bodies such as pollen, dust mites and cigarette smoke. The body,in effect, overreacts to the presence of these foreign bodies in theairways. As part of the asthmatic reaction, an increase in mucousproduction is often triggered, exacerbating airway restriction. Smoothmuscle surrounding the airways goes into spasm, resulting inconstriction of airways. The airways also become inflamed. Over time,this inflammation can lead to scarring of the airways and a furtherreduction in airflow. This inflammation leads to the airways becomingmore irritable, which may cause an increase in coughing and increasedsusceptibility to asthma episodes.

Two medicinal strategies exist for treating this problem for patientswith asthma. The condition is typically managed by means of inhaledmedications that are taken after the onset of symptoms, or by injectedand/or oral medication that are taken chronically. The medicationstypically fall into two categories; those that treat the inflammation,and those that treat the smooth muscle constriction. The first is toprovide anti-inflammatory medications, like steroids, to treat theairway tissue, reducing its tendency to over-release the molecules thatmediate the inflammatory process. The second strategy is to provide asmooth muscle relaxant (e.g. an anticholinergic) to reduce the abilityof the muscles to constrict.

It has been highly preferred that patients rely on avoidance of triggersand anti-inflammatory medications, rather than on the bronchodilators astheir first line of treatment. For some patients, however, thesemedications, and even the bronchodilators are insufficient to stop theconstriction of their bronchial passages, and more than five thousandpeople suffocate and die every year as a result of asthma attacks.

Anaphylaxis likely ranks among the other airway occluding disorders ofthis type as the most deadly, claiming many deaths in the United Statesevery year. Anaphylaxis (the most severe form of which is anaphylacticshock) is a severe and rapid systemic allergic reaction to an allergen.Minute amounts of allergens may cause a life-threatening anaphylacticreaction. Anaphylaxis may occur after ingestion, inhalation, skincontact or injection of an allergen. Anaphylactic shock usually resultsin death in minutes if untreated. Anaphylactic shock is a lifethreatening medical emergency because of rapid constriction of theairway. Brain damage sets in quickly without oxygen.

The triggers for these fatal reactions range from foods (nuts andshellfish), to insect stings (bees), to medication (radio contrasts andantibiotics). It is estimated that 1.3 to 13 million people in theUnited States are allergic to venom associated with insect bites; 27million are allergic to antibiotics; and 5-8 million suffer foodallergies. All of these individuals are at risk of anaphylactic shockfrom exposure to any of the foregoing allergens. In addition,anaphylactic shock can be brought on by exercise. Yet all are mediatedby a series of hypersensitivity responses that result in uncontrollableairway occlusion driven by smooth muscle constriction, and dramatichypotension that leads to shock. Cardiovascular failure, multiple organischemia, and asphyxiation are the most dangerous consequences ofanaphylaxis.

Anaphylactic shock requires advanced medical care immediately. Currentemergency measures include rescue breathing; administration ofepinephrine; and/or intubation if possible. Rescue breathing may behindered by the closing airway but can help if the victim stopsbreathing on his own. Clinical treatment typically consists ofantihistamines (which inhibit the effects of histamine at histaminereceptors) which are usually not sufficient in anaphylaxis, and highdoses of intravenous corticosteroids. Hypotension is treated withintravenous fluids and sometimes vasoconstrictor drugs. Forbronchospasm, bronchodilator drugs such as salbutamol are employed.

Given the common mediators of both asthmatic and anaphylacticbronchoconstriction, it is not surprising that asthma sufferers are at aparticular risk for anaphylaxis. Still, estimates place the numbers ofpeople who are susceptible to such responses at more than 40 million inthe United States alone.

Tragically, many of these patients are fully aware of the severity oftheir condition, and die while struggling in vain to manage the attackmedically. Many of these incidents occur in hospitals or in ambulances,in the presence of highly trained medical personnel who are powerless tobreak the cycle of inflammation and bronchoconstriction (andlife-threatening hypotension in the case of anaphylaxis) affecting theirpatient.

Unfortunately, prompt medical attention for anaphylactic shock andasthma are not always available. For example, epinephrine is not alwaysavailable for immediate injection. Even in cases where medication andattention is available, life saving measures are often frustratedbecause of the nature of the symptoms. Constriction of the airwaysfrustrates resuscitation efforts, and intubation may be impossiblebecause of swelling of tissues.

Typically, the severity and rapid onset of anaphylactic reactions doesnot render the pathology amenable to chronic treatment, but requiresmore immediately acting medications. Among the most popular medicationsfor treating anaphylaxis is epinephrine, commonly marketed in so-called“Epipen” formulations and administering devices, which potentialsufferers carry with them at all times. In addition to serving as anextreme bronchodilator, epinephrine raises the patient's heart ratedramatically in order to offset the hypotension that accompanies manyreactions. This cardiovascular stress can result in tachycardia, heartattacks and strokes.

Chronic obstructive pulmonary disease (COPD) is a major cause ofdisability, and is the fourth leading cause of death in the UnitedStates. More than 12 million people are currently diagnosed with COPD.An additional 12 million likely have the disease and don't even know it.COPD is a progressive disease that makes it hard for the patient tobreathe. COPD can cause coughing that produces large amounts of mucus,wheezing, shortness of breath, chest tightness and other symptoms.Cigarette smoking is the leading cause of COPD, although longtermexposure to other lung irritants, such as air pollution, chemical fumesor dust may also contribute to COPD. In COPD, less air flows in and outof the bronchial airways for a variety of reasons, including loss ofelasticity in the airways and/or air sacs, inflammation and/ordestruction of the walls between many of the air sacs and overproductionof mucus within the airways.

The term COPD includes two primary conditions: emphysema and chronicobstructive bronchitis. In emphysema, the walls between many of the airsacs are damaged, causing them to lose their shape and become floppy.This damage also can destroy the walls of the air sacs, leading to fewerand larger air sacs instead of many tiny ones. In chronic obstructivebronchitis, the patient suffers from permanently irritated and inflamedbronchial tissue that is slowly and progressively dying. This causes thelining to thicken and form thick mucus, making it hard to breathe. Manyof these patients also experience periodic episodes of acute airwayreactivity (i.e., acute exacerbations), wherein the smooth musclesurrounding the airways goes into spasm, resulting in furtherconstriction and inflammation of the airways. Acute exacerbations occur,on average, between two and three times a year in patients with moderateto severe COPD and are the most common cause of hospitalization in thesepatients (mortality rates are 11%). Frequent acute exacerbations of COPDcause lung function to deteriorate quickly, and patients never recoverto the condition they were in before the last exacerbation. Similar toasthma, current medical management of these acute exacerbations is ofteninsufficient.

Unlike cardiac arrhythmias, which can be treated chronically withpacemaker technology, or in emergent situations with equipment likedefibrillators (implantable and external), there is virtually nocommercially available medical equipment that can chronically reduce thebaseline sensitivity of the smooth muscle tissue in the airways toreduce the predisposition to asthma attacks, reduce the symptoms of COPDor to break the cycle of bronchial constriction associated with an acuteasthma attack or anaphylaxis.

Therefore, there is a need in the art for new products and methods fortreating the immediate symptoms of bronchial constriction resulting frompathologies such as anaphylactic shock, asthma and COPD. In particular,there is a need in the art for non-invasive devices and methods to treatthe immediate symptoms of bronchial constriction. Potential advantagesof such non-invasive medical methods and devices relative to comparableinvasive procedures are as follows. The patient may be morepsychologically prepared to experience a procedure that is non-invasiveand may therefore be more cooperative, resulting in a better outcome.Non-invasive procedures may avoid damage of biological tissues, such asthat due to bleeding, infection, skin or internal organ injury, bloodvessel injury, and vein or lung blood clotting. Non-invasive proceduresare generally painless and may be performed without the need for evenlocal anesthesia. Less training may be required for use of non-invasiveprocedures by medical professionals. In view of the reduced riskordinarily associated with non-invasive procedures, some such proceduresmay be suitable for use by the patient or family members at home or byfirst-responders at home or at a workplace, and the cost of non-invasiveprocedures may be reduced relative to comparable invasive procedures.

SUMMARY OF THE INVENTION

The present invention involves products and methods for the treatment ofasthma, COPD, anaphylaxis, and other pathologies involving theconstriction of the primary airways, utilizing an energy source(comprising electrical and/or magnetic, mechanical and/or acoustic, andoptical and/or thermal energy), that may be transmitted non-invasivelyto, or in close proximity to, a selected nerve to temporarily stimulate,block and/or modulate the signals in the selected nerve. The presentinvention is particularly useful for the acute relief of symptomsassociated with bronchial constriction, i.e., asthma attacks, COPDexacerbations and/or anaphylactic reactions. The teachings of thepresent invention provide an emergency response to such acute symptoms,by producing immediate airway dilation and/or heart function increase toenable subsequent adjunctive measures (such as the administration ofepinephrine) to be effectively employed.

In one aspect of the present invention, a method of treating bronchialconstriction comprises stimulating selected nerve fibers responsible forreducing the magnitude of constriction of smooth bronchial muscle toincrease the activity of the selected nerve fibers.

In a preferred embodiment, the selected nerve fibers comprise those thatsend a parasympathetic, afferent vagal signal to the brain, which thentriggers an efferent sympathetic signal to stimulate the release ofcatecholamines (comprising endogenous beta-agonists, epinephrine and/ornorepinephrine) from the adrenal glands and/or from nerve endings thatare distributed throughout the body. In yet other embodiments, themethod includes stimulating, inhibiting, blocking or otherwisemodulating other nerves that release systemic bronchodilators or nervesthat directly modulate parasympathetic ganglia transmission (bystimulation or inhibition of preganglionic to postganglionictransmissions). In an alternative embodiment, the fibers responsible forbronchodilation are interneurons that are completely contained withinthe walls of the bronchial airways. These interneurons are responsiblefor modulating the cholinergic nerves in the bronchial passages. In thisembodiment, the increased activity of the interneurons will causeinhibition or blocking of the cholinergic nerves responsible forbronchial constriction, thereby facilitating opening of the airways.

The stimulating step is preferably carried out without substantiallystimulating excitatory nerve fibers, such as parasympathetic cholinergicnerve fibers, that are responsible for increasing the magnitude ofconstriction of smooth muscle. In this manner, the activity of the nervefibers responsible for bronchodilation are increased without increasingthe activity of the cholinergic fibers which would otherwise inducefurther constriction of the smooth muscle. Alternatively, the method maycomprise the step of actually inhibiting or blocking these cholinergicnerve fibers such that the nerves responsible for bronchodilation arestimulated while the nerves responsible for bronchial constriction areinhibited or completely blocked. This blocking/inhibiting signal may beseparately applied to the inhibitory nerves; or it may be part of thesame signal that is applied to the nerve fibers responsible forbronchodilation.

In an alternative embodiment, a method of treating bronchialconstriction comprises stimulating, inhibiting, blocking or otherwisemodulating selected efferent sympathetic nerves responsible formediating bronchial passages either directly or indirectly. The selectedefferent sympathetic nerves may be nerves that directly innervate thebronchial smooth muscles. It has been postulated that asthma patientstypically have more sympathetic nerves that directly innervate thebronchial smooth muscle than individuals that do not suffer from asthma.

In another aspect of the invention, a method of treating bronchialconstriction includes applying an energy impulse to a target region inthe patient and acutely reducing the magnitude of bronchial constrictionin the patient. The energy impulse is transmitted non-invasively from anenergy source, comprising electrical and/or magnetic, mechanical and/oracoustic, and optical and/or thermal sources of energy. As used herein,the term acutely means that the energy impulse immediately begins tointeract with one or more nerves to produce a response in the patient.The energy impulse is preferably sufficient to promptly andquantitatively ameliorate a symptom, for example, to increase the ForcedExpiratory Volume in about 1 second (FEV₁) of the patient by aclinically significant amount in a period of time less than about 6hours, preferably less than about 3 hours and more preferably less thanabout 90 minutes and even more preferably less that about 15 minutes. Aclinically significant amount is defined herein as at least an about 12%increase in the patient's FEV₁ versus the FEV₁ measured prior toapplication of the energy impulse. In an exemplary embodiment, theenergy impulse is sufficient to increase the FEV₁ by at least about 19%over the FEV₁ as predicted.

In another aspect of the invention, a method for treating bronchialconstriction comprises applying one or more energy impulse(s) of afrequency from about 15 Hz to about 50 Hz to a selected region within apatient to reduce a magnitude of constriction of bronchial smoothmuscle. In a preferred embodiment, the method includes positioning thecoil of a magnetic stimulator non-invasively on or above a patient'sneck and applying a magnetically-induced electrical impulsenon-invasively to the target region within the neck to stimulate,inhibit or otherwise modulate selected nerve fibers that interact withbronchial smooth muscle. Preferably, the target region is adjacent to,or in close proximity with, the carotid sheath.

In one embodiment of the present invention, the source of stimulationenergy is a magnetic stimulator that preferably operates to induce anelectrical signal within the tissue, where the induced electrical signalhas a frequency from about 1 Hz to about 3000 Hz, a pulse duration frombetween about 10 to about 1000 microseconds, and an amplitude from about1 to about 20 volts. The induced electrical signal may be one or moreof: a full or partial sinusoid, a square wave, a rectangular wave, andtriangle wave. By way of example, the at least one induced electricalsignal may be of a frequency from about 15 Hz to about 35 Hz. By way ofexample, at least one induced electrical signal may have a pulsedon-time from about 50 to about 1000 microseconds, such as from about 100to about 300 microseconds, or about 200 microseconds. By way of example,the at least one induced electrical signal may have an amplitude fromabout 5 to about 15 volts, such as about 12 volts.

Applicant has made the unexpected discovered that applying an electricalimpulse to a selected region of a patient's neck within this particularfrequency range results in almost immediate and significant improvementin bronchodilation, as discussed in further detail below. Applicant hasfurther discovered that applying electrical impulses outside of theselected frequency range (from about 15 Hz to about 50 Hz) does notresult in significant improvement and, in some cases, may worsen thepatient's bronchoconstriction. Preferably, the frequency is about 25 Hz.In this embodiment, the electrical impulse(s) have an amplitude fromabout 0.5 to about 12 volts and have a pulsed on-time from about 50 toabout 500 microseconds, preferably from about 200 to about 400microseconds. The preferred voltage will depend on the size and shape ofthe apparatus used to deliver the electrical impulse and the distancebetween that apparatus and the target nerves. In certain embodiments theelectrical impulse preferably has an amplitude of at least about 6 voltsand more preferably from about 7 to about 12 volts. In other embodimentsthe amplitude is preferably lower, i.e., less than about 6 volts andmore preferably from about 0.1 to about 2 volts.

The energy impulse(s) are applied in a manner that reduces theconstriction of the smooth muscle lining the bronchial passages torelieve the spasms that occur during anaphylactic shock, acuteexacerbations of COPD or asthma attacks. In some embodiments, themechanisms by which the appropriate impulse is applied to the selectedregion within the patient include positioning a magnetic stimulator coilnon-invasively on or above the patient's neck in the vicinity of thenervous tissue controlling the pulmonary and/or cardiac muscles, whichcoil is coupled to an external magnetic impulse/eddy-current generatingdevice. The electric field and/or eddy-currents induced by the coil ofthe magnetic stimulator creates a field of effect that permeates thetarget nerve fibers and causes the stimulating, blocking and/ormodulation of signals to the subject smooth muscles, and/or the blockingand/or affecting of histamine response. It shall be understood thatleadless impulses as shown in the art may be utilized for applyingimpulses to the target regions.

In other embodiments, a magnetic stimulator coil is positionednon-invasively on or above an anatomical location other than thepatient's neck, in the vicinity of nervous tissue controllingbronchodilation, which coil is coupled to an external magnetic-fieldimpulse/eddy-current impulse generating device. The electromagneticfield and/or eddy-currents induced as energy impulses by the coil of themagnetic stimulator create a field of effect that permeates the targetnerve fibers and cause the stimulating, blocking, and/or modulation ofsignals to the subject smooth muscles, and/or the blocking and/oraffecting of histamine response.

In other embodiments, the mechanisms by which the appropriate energyimpulse is applied to the selected region within the patient comprisepositioning a mechanical or acoustical vibrator (ormechanical-vibration/sound conducting form-fitting garment)non-invasively, on or above the patient's neck, on or above thepatient's ear or ear-canal orifice, or on or above some other anatomicallocation in the vicinity of nervous tissue controlling bronchodilation,which mechanical or acoustical vibrator is coupled to an externalmechanical-impulse or sound-impulse generating device. The mechanical oracoustical vibrations transmitted non-invasively by the vibrator createsa field of effect that permeates the target nerve fibers and cause thestimulating, blocking, and/or modulation of signals to the subjectsmooth muscles, and/or the blocking and/or affecting of histamineresponse.

In other embodiments, the mechanisms by which the appropriate energyimpulse is applied to the selected region within the patient comprisepositioning a light or heat emitting device (or a light-conducting orheat-conducting form-fitting garment) non-invasively, on or above thepatient's ear or ear-canal orifice, or on or above some other anatomicallocation in the vicinity of nervous tissue controlling bronchodilation,which light or heat emitting device is coupled to an external light orheat generating source, said source being a device that can generatelight or heat as impulses of energy corresponding to electromagneticradiation having wavelengths in the infra-red, far-infrared, visible, orultra-violet ranges of electromagnetic radiation (having wavelengths inthe range of about 10-8 meters to about 10-3 meters, inclusive). Thelight or heat transmitted non-invasively from the light or heat emittingdevice creates a field of effect that permeates the target nerve fibersand cause the stimulating, blocking, and/or modulation of signals to thesubject smooth muscles, and/or the blocking and/or affecting ofhistamine response.

In other embodiments, the mechanisms by which the appropriate energyimpulse is applied to the selected region within the patient comprisepositioning the distal ends of one or more electrical lead (orelectrically conducting form-fitting garment) non-invasively, on orabove the patient's neck, on or above the patient's ear or ear-canalorifice, or on or above some other anatomical location in the vicinityof nervous tissue controlling bronchodilation, which lead or leads arecoupled to an external electrical impulse generating device, for examplevia an electrode. The electric field generated non-invasively at thedistal tip of the lead creates a field of effect that permeates thetarget nerve fibers and cause the stimulating, blocking, and/ormodulation of signals to the subject smooth muscles, and/or the blockingand/or affecting of histamine response.

The novel systems, devices and methods for treating bronchialconstriction are more completely described in the following detaileddescription of the invention, with reference to the drawings providedherewith, and in claims appended hereto. Other aspects, features,advantages, etc. will become apparent to one skilled in the art when thedescription of the invention herein is taken in conjunction with theaccompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference. If anydisclosures are incorporated herein by reference and such disclosuresconflict in part and/or in whole with the present disclosure, then tothe extent of conflict, and/or broader disclosure, and/or broaderdefinition of terms, the present disclosure controls. If suchdisclosures conflict in part and/or in whole with one another, then tothe extent of conflict, the later-dated disclosure controls.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 is a schematic view of a nerve modulating device according to thepresent invention, which supplies controlled pulses of electricalcurrent to a magnetic stimulator coil.

FIG. 2 illustrates an exemplary electrical voltage/current profile for ablocking and/or modulating impulse applied to a portion or portions of anerve in accordance with an embodiment of the present invention.

FIG. 3 is a schematic view of an alternate embodiment of a nervemodulating device according to the present invention, which suppliescontrolled pulses of electrical current to a linear actuator that isused as a mechanical vibrator.

FIG. 4 is a schematic view of an alternate embodiment of a nervemodulating device according to the present invention, which controls theemission of pulses of light from an earplug.

FIGS. 5-14 graphically illustrate exemplary experimental data obtainedon guinea pigs in accordance with multiple embodiments of the presentinvention.

FIGS. 15-18 graphically illustrate exemplary experimental data obtainedon human patients in accordance with multiple embodiments of the presentinvention.

FIGS. 19-24 graphically illustrate the inability of signals taught byU.S. patent application Ser. No. 10/990,938 to achieve the results ofthe present invention.

FIGS. 25 and 26 graphically illustrates the inability of signals taughtby International Patent Application Publication Number WO 93/01862 toachieve the results of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, energy is transmitted non-invasively to apatient. Transmission of energy is defined herein to mean themacroscopic transfer of energy from one point to another point through amedium, including possibly a medium that is free space, such that ingoing from a point of origin to a point of destination, the energy istransferred successively to the medium at points along a path connectingthe points of origin and destination. Some energy at the point of originwill ordinarily be lost to the medium before arriving at the point ofdestination. If energy is radiated in all directions from the point oforigin, then only that energy following a path from the point of originto the destination point is considered to be transmitted. According tothis definition, electrical, magnetic, electromagnetic, mechanical,acoustical, and thermal energy may be transmitted. But chemical energyin the form of chemical bonds would ordinarily not fall under thisdefinition of energy transmission, because when moving macroscopicallybetween two points, e.g., by diffusion, the energy contained withinchemical bonds would not ordinarily be transferred to a medium atintervening points. Thus, the diffusion of chemical substances wouldordinarily be considered to be a flux of mass (kg·m−2·s−1) rather than aflux of energy (J·m−2·s−1).

One aspect of the present invention teaches non-invasive methods fortreating bronchial constriction by stimulating selected nerve fibersthat are responsible for reducing the magnitude of constriction ofsmooth bronchial muscle, such that the activity of those selected nervefibers is increased and smooth bronchial muscle is dilated. Prominentamong such nerve fibers are some that are associated with the vagusnerve.

As described below in connection with different embodiments of thepresent invention, non-invasive methods involving the transmission ofmagnetic and/or electrical energy as well as mechanical and/or acousticenergy have been used to stimulate nerves that could be responsible forbronchodilation, particularly the vagus nerve. However, to the knowledgeof the present applicants, they have never been performed in such a wayas to achieve bronchodilation. Conversely, energy has been applied topatients in such a way as to bring about bronchodilation, but thoseapplications involve methods that are invasive, not non-invasive. Forexample, U.S. Pat. No. 7,740,017, entitled Method for treating an asthmaattack, to Danek et al., discloses an invasive method for directingradio frequency energy to the lungs to bring about bronchodilation. U.S.Pat. No. 7,264,002, entitled Methods of treating reversible obstructivepulmonary disease, to Danek et al., discloses methods of treating anasthmatic lung invasively, by advancing a treatment device into the lungand applying energy. Those invasive methods attempt to dilate thebronchi directly, rather than to stimulate nerve fibers that in turnbring about bronchodilation. However, our own experiments, which aredescribed below, demonstrate that minimally invasive electricalstimulation of nerve fibers can in fact achieve bronchodilation. Theymotivate the present application that discloses several methods anddevices to stimulate such nerve fibers non-invasively, in order toproduce bronchodilation.

In the preferred embodiments, a time-varying magnetic field originatingoutside of a patient is applied to a patient, such that the magneticfield generates an electromagnetic field and/or induces eddy currentswithin tissue of the patient. The invention is particularly useful forinducing applied electrical impulses that interact with the signals ofone or more nerves, or muscles, to achieve a therapeutic result, such asrelaxation of the smooth muscle of the bronchia. In particular, thepresent invention provides methods and devices for immediate relief ofacute symptoms associated with bronchial constriction such as asthmaattacks, COPD exacerbations and/or anaphylactic reactions.

For convenience, much of the remaining disclosure will be directedspecifically to treatment in or around the carotid sheath with devicespositioned non-invasively on or near a patient's neck, but it will beappreciated that the systems and methods of the present invention can beapplied equally well to other tissues and nerves of the body, includingbut not limited to other parasympathetic nerves, sympathetic nerves,spinal or cranial nerves. In addition, the present invention can be usedto directly or indirectly stimulate or otherwise modulate nerves thatinnervate bronchial smooth muscle. While the exact physiological causesof asthma, COPD and anaphylaxis have not been determined, the presentinvention postulates that the direct mediation of the smooth muscles ofthe bronchia is the result of activity in one or more nerves near or inthe carotid sheath. In the case of asthma, it appears that the airwaytissue has both (i) a hypersensitivity to the allergen that causes theoverproduction of the cytokines that stimulate the cholinergic receptorsof the nerves and/or (ii) a baseline high parasympathetic tone or a highramp up to a strong parasympathetic tone when confronted with any levelof cholenergic cytokine. The combination can be lethal. Anaphylaxisappears to be mediated predominantly by the hypersensitivity to anallergen causing the massive overproduction of cholenergic receptoractivating cytokines that overdrive the otherwise normally operatingvagus nerve to signal massive constriction of the airways. Drugs such asepinephrine drive heart rate up while also relaxing the bronchialmuscles, effecting temporary relief of symptoms from these conditions.Experience has shown that severing the vagus nerve (an extreme versionof reducing the parasympathetic tone) has an effect similar to that ofepinephrine on heart rate and bronchial diameter in that the heartbegins to race (tachycardia) and the bronchial passageways dilate. Oneaspect of the present invention is that it may produce an effect similarto that of epinephrine in relaxing the contraction of smooth muscle inbronchial passageways. However, the present invention is not intended toreverse hypersensitivity to an allergen or to modulate the production ofcytokines.

To investigate the mechanism by which vagal (or vagus) nerve stimulation(VNS) can result in bronchodilation, the present applicant andcolleagues performed experiments that are reported herein [published asconference proceedings: Bruce J. SIMON, Charles W. Emala, Lawrence M.Lewis, Daniel Theodoro, Yanina Purim-Shem-Tov, Pedro Sepulveda, ThomasJ. Hoffmann, Peter Staats. Vagal Nerve Stimulation for Relief ofBronchoconstriction: Preliminary Clinical Data and Mechanism of Action.Proceedings page 119 of Neuromodulation: 2010 and Beyond; North AmericanNeuromodulation Society 13th Annual Meeting, Dec. 3-6, 2009]. Theexperiments are described in detail later in the present application,but the following is a summary of their design, results, andinterpretation.

Animal studies were first performed. Under IACUC approved protocols,male Hartley guinea pigs were anesthetized with i.p. urethane andventilated through a tracheostomy. Bronchoconstriction was induced viaiv histamine or acetylcholine with or without simultaneous, bilateralVNS at 25 Hz, 200 ms, 1-3 V. Selective antagonists (L-NAME/iNANC,propranolol/sympathetic) and vagal ligation were used to elucidate theneural pathways responsible for the bronchodilation response. Theresults of these animal studies were as follows. Ligating both vagusnerves caudal to the stimulating electrodes did not block theVNS-mediated attenuation of bronchoconstriction while ligating rostrallydid block the attenuation of bronchoconstriction. This suggests that themechanism was mediated through an afferent neural pathway. Blockade ofnitric oxide synthesis by pretreatment with L-NAME (a primary mediatorof inhibitory non-adrenergic, non-cholinergic (iNANC) bronchodilatorpathways) had no effect on VNS-mediated attenuation ofbronchoconstriction while pretreatment with propranolol reversiblyblocked the effect.

Human studies were also performed. Under an FDA IDE with IRB approval,six adult patients were studied who were seen in the emergencydepartment for moderate to severe asthma (FEV1 16%-69%) and who failedto respond to conventional pharmacologic therapy, includingβ2-adrenergic receptor agonists (6/6) and oral steroid treatment (5/6).Following consent, patients were prepped, draped, and using only localanesthesia, underwent percutaneous placement of an electrode lead in thevicinity of the carotid sheath, assisted by ultrasound guidance.Treatment consisted of up to 180 minutes of continuous electricalstimulation at 25 Hz, 200 ms, 1-12 V. Benefit was determined by changesin FEV1. The results of these clinical studies were as follows. Within30 minutes of VNS therapy, the mean % predicted FEV1 increased from49.8±7.8 to 58.8±7.5 (p=0.003). FEV1 continued to improve duringtreatment (mean maximum increase of ˜44%) and benefit remained aftertreatment ended (at 30 minutes post, % predicted FEV1 was 67.1±8.1,p=0.004). There were no episodes of hypotension, bradycardia,diaphoresis, or increased tachycardia during stimulation, norcomplications within the one week follow-up.

We therefore conclude the following from the animal and clinicalstudies. Preliminary data suggests that VNS can safely inducesignificant bronchodilation in humans during an exacerbation of asthmain those who with a poor response to standard pharmacological treatment.Preliminary animal data indicates that VNS activates afferent nerves andmay act through a sympathetic reflex pathway to mediate bronchodilation.Thus, we found that bronchodilation resulting from stimulation of thevagus nerve works by causing the systemic release of the natural,endogenous β-agonists, epinephrine and norepinephrine. Thesecatecholamines can reach the constricted bronchial smooth muscle throughan internal, systemic pathway, thereby overcoming any potential problemswith inhaled β-agonists, for example, due to mucus congestion. Theelectrical field delivered to the vagus nerve was optimized to stimulatethe release of these hormones into the circulation at concentrationsthat produce bronchial smooth muscle relaxation, but have little effecton heart rate or blood pressure. The data suggest that the release ofthese catecholamines is mediated by a parasympathetic, afferent vagalsignal to the brain, which then triggers an efferent sympathetic signalto stimulate the release of catecholamines from the adrenal glands.These animal data show that the stimulator is effective even if thevagus nerve is tied off distal to the electrode and that thebronchodilation effect can be blocked with the β-blocker propranolol. Inaddition, stimulation was found to be ineffective in animals that havehad their adrenal glands removed.

In accordance with the present invention, the delivery, in a patientsuffering from severe asthma, COPD or anaphylactic shock, of an impulseof energy sufficient to stimulate, block and/or modulate transmission ofsignals of selected nerve fibers will result in relaxation of thebronchi smooth muscle, dilating airways and/or counteract the effect ofhistamine on the vagus nerve. Depending on the placement of the impulse,the stimulating, blocking and/or modulating signal can also raise theheart function.

Stimulating, blocking and/or modulating the signal in selected nerves toreduce parasympathetic tone provides an immediate emergency response,much like a defibrillator, in situations of severe asthma or COPDattacks or anaphylactic shock, providing immediate temporary dilation ofthe airways and optionally an increase of heart function untilsubsequent measures, such as administration of epinephrine, rescuebreathing and intubation can be employed. Moreover, the teachings of thepresent invention permit immediate airway dilation and/or heart functionincrease to enable subsequent life saving measures that otherwise wouldbe ineffective or impossible due to severe constriction or otherphysiological effects. Treatment in accordance with the presentinvention provides bronchodilation and optionally increased heartfunction for a long enough period of time so that administeredmedication such as epinephrine has time to take effect before thepatient suffocates.

In a preferred embodiment, a method of treating bronchial constrictioncomprises stimulating selected nerve fibers responsible for reducing themagnitude of constriction of smooth bronchial muscle to increase theactivity of the selected nerve fibers. Certain signals of theparasympathetic nerve fibers cause a constriction of the smooth musclesurrounding the bronchial passages, while other signals of theparasympathetic nerve fibers carry the opposing signals that tend toopen the bronchial passages. Specifically, it should be recognized thatcertain signals, such as cholinergic fibers mediate a response similarto that of histamine, while other signals generate an effect similar toepinephrine. [CANNING, Brendan J. Reflex regulation of airway smoothmuscle tone. J Appl Physiol 101: 971-985, 2006.] As described inconnection with our experiments summarized above, the latter fibersinclude those that may directly or indirectly cause the systemic releaseof catecholamines from the adrenal glands and/or from nerve endingsdistributed throughout the body, so in what follows, those latter fiberswill be called collectively “epinephrine-like-effect” fibers. Repeatedstimulation of some such fibers may cause the repeated pulsatilesystemic release of epinephrine (and/or other catecholamies), leadingeventually to circulating steady state concentrations of catecholaminesthat are determined by the stimulation frequency as well as thehalf-life of circulating catecholamines. Given the postulated balancebetween these signals, stimulating the “epinephrine-like-effect” nervefibers and/or blocking or removing the cholinergic signals should createan imbalance emphasizing bronchodilation.

In one embodiment of the present invention, the selected nerve fibersare “epinephrine-like-effect” nerve fibers which are generallyresponsible for bronchodilation. Stimulation of these“epinephrine-like-effect” fibers increases their activity, therebyincreasing bronchodilation and facilitating opening of the airways ofthe mammal. The stimulation may occur through direct stimulation of theefferent “epinephrine-like-effect” fibers that cause bronchodilation orindirectly through stimulation of the afferent sympathetic orparasympathetic nerves which carry signals to the brain and then backdown through the “epinephrine-like-effect” nerve fibers to the bronchialpassages.

In certain embodiments, the “epinephrine-like-effect” nerve fibers areassociated with the vagus nerve and are thus directly responsible forbronchodilation. Alternatively, the “epinephrine-like-effect” fibers maybe interneurons that are completely contained within the walls of thebronchial airways. These interneurons are responsible for modulating thecholinergic nerves in the bronchial passages. In this embodiment, theincreased activity of the “epinephrine-like-effect” interneurons willcause inhibition or blocking of the cholinergic nerves responsible forbronchial constriction, thereby facilitating opening of the airways.

As discussed above, certain parasympathetic signals mediate a responsesimilar to histamine, thereby causing a constriction of the smoothmuscle surrounding the bronchial passages. Accordingly, the stimulatingstep of the present invention is preferably carried out withoutsubstantially stimulating the parasympathetic nerve fibers, such as thecholinergic nerve fibers associated with the vagus nerve, that areresponsible for increasing the magnitude of constriction of smoothmuscle. In this manner, the activity of the “epinephrine-like-effect”nerve fibers are increased without increasing the activity of theadrenergic fibers which would otherwise induce further constriction ofthe smooth muscle. Alternatively, the method may comprise the step ofactually inhibiting or blocking these cholinergic nerve fibers such thatthe nerves responsible for bronchodilation are stimulated while thenerves responsible for bronchial constriction are inhibited orcompletely blocked. This blocking signal may be separately applied tothe inhibitory nerves; or it may be part of the same signal that isapplied to the “epinephrine-like-effect” nerve fibers.

While it is believed that there are little to no direct sympatheticinnervations of the bronchial smooth muscle in most individuals, recentevidence has suggested asthma patients do have such sympatheticinnervations within the bronchial smooth muscle. In addition, thesympathetic nerves may have an indirect effect on the bronchial smoothmuscle.

Accordingly, alternative embodiments of the prevent inventioncontemplate a method of stimulating selected efferent sympathetic nervesresponsible for mediating bronchial passages either directly orindirectly. The selected efferent sympathetic nerves may be nerves thatdirectly innervate the smooth muscles, nerves that release systemicbronchodilators or nerves that directly modulate parasympathetic gangliatransmission (by stimulation or inhibition of preganglionic topostganglionic transmissions).

Method and devices of the present invention are particularly useful forproviding substantially immediate relief of acute symptoms associatedwith bronchial constriction such as asthma attacks, COPD exacerbationsand/or anaphylactic reactions. One of the key advantages of the presentinvention is the ability to provide almost immediate dilation of thebronchial smooth muscle in patients suffering from acutebronchoconstriction, opening the patient's airways and allowing them tobreathe and more quickly recover from an acute episode (i.e., arelatively rapid onset of symptoms that are typically not prolonged orchronic).

The magnitude of bronchial constriction in a patient is typicallyexpressed in a measurement referred to as the Forced Expiratory Volumein 1 second (FEV₁). FEV₁ represents the amount of air a patient exhales(expressed in liters) in the first second of a pulmonary function test,which is typically performed with a spirometer. The spirometer comparesthe FEV₁ result to a standard for the patient, which is based on thepredicted value for the patient's weight, height, sex, age and race.This comparison is then expressed as a percentage of the FEV₁ aspredicted. Thus, if the volume of air exhaled by a patient in the firstsecond is 60% of the predicted value based on the standard, the FEV₁will be expressed in both the actual liters exhaled and as a percentageof predicted (i.e., 60% of predicted). In practice, a baseline value ofFEV1 is measured, and after a therapeutic intervention, a second valueof FEV1 is measured in order to ascertain the efficacy of theintervention. It should be noted that interventions known to dilate thebronchi (e.g., administration of epinephrine or the teachings of thepresent invention) are most likely to succeed when the patient'sbaseline FEV1 value is in the range −1 to −5 standard deviations of thestatistical distribution of values of FEV1 for individuals in thepopulation at large. This is because if the baseline value is outsidethat range, the patient's breathing problem is less likely to be due tobronchoconstriction and more likely to be due to something else, such asinflammatory mechanisms.

Certain other measurements may act as surrogates for the measurement ofFEV₁. Those other non-invasive measurements are particularly useful forpatients who cannot cooperate to perform measurements made byspirometry, or for settings in which it is not possible to performspirometry. Because those other measurements may be used to generate anon-invasive, continuous signal that indicates the efficacy ofstimulating the selected nerves, they will be discussed below inconnection with their use to provide a feedback signal in the presentinvention, for adjusting the power of the applied impulse, as well asfor adjustment of other stimulation parameters. It should be noted herethat one of them, the interrupter technique (Rint) measures airwayresistance, which according to Poiseuille's Law for laminar air flow, isinversely proportional to the fourth power of the caliber of dilation ofthe bronchi.

The measurement of FEV₁ entails first measuring forced expiration volumeas a function of time (the maximum expiratory flow-volume curve, orMEFV, which may be depicted in different ways, e.g., normalized topercentage of vital capacity), then reading the value of the MEFV curveat the one second point. Because a single parameter such as FEV₁ cannotcharacterize the entire MEFV curve, it is understood that the MEFV curveitself (or a set of parameters derived from it) more accuratelyrepresents the patient's respiratory status than the FEV₁ value alone[Francois HAAS, Kenneth Axen, and John Salazar Schicchi. Use of MaximumExpiratory Flow-Volume Curve Parameters in the Assessment ofExercise-induced Bronchospasm. Chest 1993; 103:64-68]. Furthermore, itis understood that in order to understand the functional relationshipbetween the magnitude of bronchoconstriction (literally, a reduction inthe average caliber of bronchial lumen) and FEV₁, one does so by firstconsidering the relation of each of them to the MEFV curve [Rodney K.LAMBERT and Theodore A. Wilson. Smooth muscle dynamics and maximalexpiratory flow in asthma. J Appl Physiol 99: 1885-1890, 2005].

As will be discussed below in connection with a detailed description ofour experiments that were only summarized above, applicants havedisclosed a system and method for increasing a patient's FEV₁ in arelatively short period of time. Preferably, the impulse of energyapplied to the patient is sufficient to increase the FEV₁ of the patientby a clinically significant amount in a period of time less than about 6hours, preferably less than 3 hours and more preferably less than 90minutes. In an exemplary embodiment, the clinically significant increasein FEV₁ occurs in less than 15 minutes. A clinically significant amountis defined herein as at least a 12% increase in the patient's FEV₁versus the FEV₁ prior to application of the electrical impulse.

In the preferred embodiment of the present invention, a magneticstimulator is used to stimulate selected nerve fibers, particularly thevagus nerve. Magnetic stimulation has been used by several investigatorsto non-invasively stimulate the vagus nerve. As indicated above, suchmagnetic stimulation involves the application of a time-varying magneticfield to induce electric currents and fields within tissue. However,none of the following reports of magnetic stimulation of the vagus nervewere related to the treatment of bronchoconstriction. In a series ofarticles beginning in 1992, Aziz and colleagues describe usingnon-invasive magnetic stimulation to electrically stimulate the vagusnerve in the neck. [Q. AZIZ et al. Magnetic Stimulation of EfferentNeural Pathways to the Human Oesophagus. Gut 33: S53-S70 (Poster SessionF218) (1992); AZIZ, Q., J. C. Rothwell, J. Barlow, A. Hobson, S. Alani,J. Bancewicz, and D. G. Thompson. Esophageal myoelectric responses tomagnetic stimulation of the human cortex and the extracranial vagusnerve. Am. J. Physiol. 267 (Gastrointest. Liver Physiol. 30): G827-G835,1994; Shaheen HAMDY, Qasim Aziz, John C. Rothwell, Anthony Hobson,Josephine Barlow, and David G. Thompson. Cranial nerve modulation ofhuman cortical swallowing motor pathways. Am. J. Physiol. 272(Gastrointest. Liver Physiol. 35): G802-G808, 1997; Shaheen HAMDY, JohnC. Rothwell, Qasim Aziz, Krishna D. Singh, and David G. Thompson.Long-term reorganization of human motor cortex driven by short-termsensory stimulation. Nature Neuroscience 1 (issue 1, May 1998):64-68.]SIMS and colleagues stimulated the vagus nerve at and near the mastoidtip. [H. Steven SIMS, Toshiyuki Yamashita, Karen Rhew, and Christy L.Ludlow. Assessing the clinical utility of the magnetic stimulator formeasuring response latencies in the laryngeal muscles. Otolaryngol HeadNeck Surg 1996; 114:761-7]. KHEDR and colleagues also used a magneticstimulator to stimulate the vagus nerve at the tip of the mastoid bone[E. M. KHEDR and E-E. M. Aref Electrophysiological study of vocal-foldmobility disorders using a magnetic stimulator. European Journal ofNeurology 2002, 9: 259-267; KHEDR, E. M., Abo-Elfetoh, N., Ahmed, M. A.,Kamel, N. F., Farook, M., El Karn, M. F. Dysphagia and hemisphericstroke: A transcranial magnetic study. NeurophysiologieClinique/Clinical Neurophysiology (2008) 38, 235-242)]. SHAFIKstimulated the vagus nerve in the neck, placing the magnetic stimulatoron the neck between the sternomastoid muscle and the trachea. [A.SHAFIK. Functional magnetic stimulation of the vagus nerve enhancescolonic transit time in healthy volunteers. Tech Coloproctol (1999)3:123-12]. Among these investigations, the one by SHAFIK stimulated thevagus nerve for the longest period of time. He stimulated at 175 joulesper pulse, 40 Hz frequency, 10 seconds on, 10 seconds off for 20 minutesduration and followed by 60 minutes of rest, and this sequence wasperformed for 5 cycles in each subject. Also, in U.S. Pat. No.7,657,310, entitled Treatment of reproductive endocrine disorders byvagus nerve stimulation, to William R. Buras, there is mention ofelectrical stimulation of the vagus nerve “in combination with amagnetic signal, such as transcranial magnetic stimulation (TMS)”.However, that patent relates to invasive nerve stimulation and isunrelated to the treatment of bronchoconstriction, as are all the otherabove-mentioned magnetic stimulations of the vagus nerve.

The vagus is not the only nerve that may be stimulated non-invasively inthe neck using magnetic stimulation. For example, the phrenic nerve hasalso been magnetically stimulated. [SIMILOWSKI, T., B. Fleury, S.Launois, H. P. Cathala, P. Bouche, and J. P. Derenne. Cervical magneticstimulation: a new painless method for bilateral phrenic nervestimulation in conscious humans. J. Appl. Physiol. 67(4): 1311-1318,1989; Gerrard F. RAFFERTY, Anne Greenough, Terezia Manczur, Michael I.Polkey, M. Lou Harris, Nigel D. Heaton, Mohamed Rela, and John Moxham.Magnetic phrenic nerve stimulation to assess diaphragm function inchildren following liver transplantation. Pediatr Crit Care Med 2001,2:122-126; W. D-C. MAN, J. Moxham, and M. I. Polkey. Magneticstimulation for the measurement of respiratory and skeletal musclefunction. Eur Respir J 2004; 24: 846-860].

FIG. 1 is a schematic diagram of a nerve modulating device 300 fordelivering impulses of energy to nerves for the treatment of bronchialconstriction or hypotension associated with anaphylactic shock, COPD orasthma. As shown, device 300 may include an impulse generator 310; apower source 320 coupled to the impulse generator 310; a control unit330 in communication with the impulse generator 310 and coupled to thepower source 320; and a magnetic stimulator coil 340 coupled via wiresto impulse generator coil 310. The control unit 330 may control theimpulse generator 310 for generation of a signal suitable foramelioration of the bronchial constriction or hypotension when thesignal is applied to the nerve non-invasively via the magneticstimulator coil 340. It is noted that nerve modulating device 300 may bereferred to by its function as a pulse generator. U.S. PatentApplication Publications 2005/0075701 and 2005/0075702, both to Shafer,both of which are incorporated herein by reference, relating tostimulation of neurons of the sympathetic nervous system to attenuate animmune response, contain descriptions of pulse generators that may beapplicable to the present invention, when adapted for use with amagnetic stimulator coil.

In the preferred embodiment, the vagus nerve will be stimulated in thepatient's neck, where it is situated within the carotid sheath, near thecarotid artery and the interior jugular vein. The carotid sheath islocated at the lateral boundary of the retopharyngeal space on each sideof the neck and deep to the sternocleidomastoid muscle. The left vagusnerve is selected for stimulation because stimulation of the right vagusnerve may produce unwanted effects on the heart.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line would pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein is the preferred location for non-invasive stimulation of the vagusnerve. In the preferred embodiment, the magnetic stimulator coil wouldbe centered on such a point, at the level of about the fifth to sixthcervical vertebra.

Signal generators for magnetic stimulators have been described forcommercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006], as well as for customdesigns for a control unit 330, impulse generator 310 and power source320 [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, and Wentai Liu.Magnetic Stimulation of Neural Tissue: Techniques and System Design. pp293-352, In: Implantable Neural Prostheses 1, Devices and Applications,D. Zhou and E. Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.7,744,523, entitled Drive circuit for magnetic stimulation, to CharlesM. Epstein; U.S. Pat. No. 5,718,662, entitled Apparatus for the magneticstimulation of cells or tissue, to Reza Jalinous; U.S. Pat. No.5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, toPolson]. Magnetic nerve stimulators use a high current impulse generator310 that may produce discharge currents of 5,000 amps or more, which ispassed through the stimulator coil 340, and which thereby produces amagnetic pulse. Typically, a transformer charges a capacitor in theimpulse generator 310, which also contains circuit elements that limitthe effect of undesirable electrical transients. Charging of thecapacitor is under the control of a control unit 330, which acceptsinformation such as the capacitor voltage, power and other parametersset by the user, as well as from various safety interlocks within theequipment that ensure proper operation, and the capacitor is thendischarged through the coil via an electronic switch (e.g., a controlledrectifier) when the user wishes to apply the stimulus.

Greater flexibility is obtained by adding to the impulse generator abank of capacitors that can be discharged at different times. Thus,higher impulse rates may be achieved by discharging capacitors in thebank sequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

The control unit 330 also comprises a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard and computer mouse as wellas externally supplied physiological signals, analog-to-digitalconverters for digitizing externally supplied analog signals,communication devices for the transmission and receipt of data to andfrom external devices such as printers and modems that comprise part ofthe system, hardware for generating the display of information onmonitors that comprise part of the system, and busses to interconnectthe above-mentioned components. Thus, the user operates the systemprimarily by typing instructions for the control unit 330 at a devicesuch as a keyboard and views the results on a device such as thesystem's computer monitor, or directs the results to a printer, modem,and/or storage disk.

Parameters of stimulation include power level, frequency and trainduration (or pulse number). The stimulation characteristics of eachmagnetic pulse, such as depth of penetration, strength and accuracy,depend on the rise time, peak electrical energy transferred to the coiland the spatial distribution of the field. The rise time and peak coilenergy are governed by the electrical characteristics of the magneticstimulator and stimulating coil, whereas the spatial distribution of theinduced electric field depends on the coil geometry and the anatomy ofthe region of induced current flow. In one embodiment of the invention,pulse parameters are set in such as way as to account for the detailedanatomy surrounding the nerve that is being stimulated [Bartosz SAWICKI,Robert Szmur

o, Przemys

aw P

onecki, Jacek Starzyński, Stanis

aw Wincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, IOS Press, 2008]. Asingle pulse may be monophasic (no current reversal within the coil),biphasic or polyphasic. For rapid rate stimulators, biphasic systems areused wherein energy is recovered from each pulse in order to helpenergize the next. Embodiments of the invention include those that arefixed frequency, where each pulse in a train has the same interstimulusinterval, and those that have modulated frequency, where the intervalsbetween each pulse in a train can be varied.

Embodiments of the magnetic stimulator coil 340 include circular,parabolic, figure-of-eight (butterfly), and custom designs that areavailable commercially [Chris HOVEY and Reza Jalinous, THE GUIDE TOMAGNETIC STIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006]. Additional embodimentsof the magnetic stimulator coil 340 have been described [U.S. Pat. No.6,179,770, entitled Coil assemblies for magnetic stimulators, to StephenMould; Kent DAVEY. Magnetic Stimulation Coil and Circuit Design. IEEETransactions on Biomedical Engineering, Vol. 47 (No. 11, November 2000):1493-1499].

The preferred embodiment of magnetic stimulator coil 340 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (No. 4, April 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999. (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents desired for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface. This is difficult to do in practice because the tissuecontours (head for TMS, arms, legs, neck, etc. for peripheral nervestimulation) are not planar. To solve this problem, in the preferredembodiment of the present invention, the toroidal coil is embedded in aballoon-like structure which is filled with a conducting medium (e.g., asaline solution) with the same conductivity as muscle tissue. Thecontainer itself is made of a conducting elastomer. In other embodimentsof the invention, the conducting medium may be a balloon filled with aconducting gel or conducting powders, or the balloon may be constructedextensively from deformable conducting elastomers. The balloon conformsto the skin surface removing any air, thus allowing for high impedancematching and conduction of large electric fields in to the tissue. Adevice such as that disclosed in U.S. Pat. No. 7,591,776, entitledMagnetic stimulators and stimulating coils, to Phillips et al. mayconform the coil itself to the contours of the body, but in thepreferred embodiment, such a curved coil is also enclosed by a containerthat is filled with a conducting medium.

The container of electrically conducting medium is identified as 350 inFIG. 1. As shown there, the container of electrically conducting medium350 not only encloses the magnetic stimulator coil, but in the preferredembodiment is also deformable such that it is form-fitting when appliedto the surface of the body. Thus, the sinuousness or curvature shown atthe outer surface of the container of electrically conducting medium 350correspond also to sinuousness or curvature on the surface of the body,against which the container 350 is applied so as to make the containerand body surface contiguous. Use of the container of conducting medium350 allows one to generate (induce) electric fields in tissue (andelectric field gradients and electric currents) that are equivalent tothose generated using current magnetic stimulation devices, but with1/10 to 1/1000 of the current applied to the magnetic coil. This allowsfor minimal heating and deeper tissue stimulation.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators can take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY R K, So Y T,Goodin D S, Aminoff M J. A comparison of magnetic and electricstimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.NILSSON, M. Panizza, B. J. Roth et al. Determining the site ofstimulation during magnetic stimulation of the peripheral nerve,Electroencephalographs and clinical neurophysiology. vol 85, pp.253-264, 1992; Nafia AL-MUTAWALY, Hubert de Bruin, and Gary Hasey. TheEffects of Pulse Configuration on Magnetic Stimulation. Journal ofClinical Neurophysiology 20(5):361-370, 2003].

Furthermore, a potential practical disadvantage of using magneticstimulator coils is that they may overheat when used over an extendedperiod of time. Use of the above-mentioned toroidal coil and containerof electrically conducting medium addresses this potential disadvantage.However, because of the poor coupling between the stimulating coils andthe nerve tissue, large currents are nevertheless desired to reachthreshold electric fields. At high repetition rates, these currents canheat the coils to unacceptable levels in seconds to minutes depending onthe power levels and pulse durations and rates. Two approaches toovercome heating are to cool the coils with flowing water or air or toincrease the magnetic fields using ferrite cores (thus allowing smallercurrents). For some applications where relatively long treatment timesat high stimulation frequencies may be desired, e.g. treating acuteasthma attacks by stimulating the vagus nerve, neither of these twoapproaches are adequate. Water-cooled coils overheat in a few minutes.Ferrite core coils heat more slowly due to the lower currents and heatcapacity of the ferrite core, but also cool off more slowly and do notallow for water-cooling since the ferrite core takes up the volume wherethe cooling water would flow.

A solution to this problem is to use a fluid which containsferromagnetic particles in suspension like a ferrofluid, ormagnetorheological fluid as the cooling material. Ferrofluids arecolloidal mixtures composed of nanoscale ferromagnetic, orferrimagnetic, particles suspended in a carrier fluid, usually anorganic solvent or water. The ferromagnetic nanoparticles are coatedwith a surfactant to prevent their agglomeration (due to van der Waalsforces and magnetic forces). Ferrofluids have a higher heat capacitythan water and will thus act as better coolants. In addition, the fluidwill act as a ferrite core to increase the magnetic field strength.Also, since ferrofluids are paramagnetic, they obey Curie's law, andthus become less magnetic at higher temperatures. The strong magneticfield created by the magnetic stimulator coil will attract coldferrofluid more than hot ferrofluid thus forcing the heated ferrofluidaway from the coil. Thus, cooling may not require pumping of theferrofluid through the coil, but only a simple convective system forcooling. This is an efficient cooling method which may require noadditional energy input [U.S. Pat. No. 7,396,326 and publishedapplications US2008/0114199, US2008/0177128, and US2008/0224808, allentitled Ferrofluid cooling and acoustical noise reduction in magneticstimulators, respectively to Ghiron et al., Riehl et al., Riehl et al.and Ghiron et al.].

Magnetorheological fluids are similar to ferrofluids but contain largermagnetic particles which have multiple magnetic domains rather than thesingle domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magnetosensitive fluid composition and a process for preparation thereof, toJohn et al.]. They can have a significantly higher magnetic permeabilitythan ferrofluids and a higher volume fraction of iron to carrier.Combinations of magnetorheological and ferrofluids may also be used [M TLOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D GDuran. Magnetorheology for suspensions of solid particles dispersed inferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; LadislauVEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Scienceand Technology Vol. 54 (2008) pp 127-136.]. Accordingly, in thepreferred embodiment, overheating is minimized by cooling the magneticstimulator coil 340 with a ferrofluid and/or magnetorheological fluidand/or a mixture or combination of ferrofluid and magnetorheologicalfluids.

In the preferred embodiment, overheating of the magnetic stimulator coil340 may also be minimized by optionally restricting the magneticstimulation to particular phases of the respiratory cycle, allowing thecoil to cool during the other phases of the respiratory cycle.Alternatively, greater peak power may be achieved per respiratory cycleby concentrating all the energy of the magnetic pulses into selectedphases of the respiratory cycle. Detection of the phase of respirationmay be performed non-invasively by adhering a thermistor or thermocoupleprobe to the patient's cheek so as to position the probe at the nasalorifice. Strain gauge signals from belts strapped around the chest, aswell as inductive plethysmography and impedance pneumography, are alsoused traditionally to non-invasively generate a signal that rises andfalls as a function of the phase of respiration. After digitizing suchsignals, the phase of respiration may be determined using open sourcesoftware such as the one called “puka”, which is part of PhysioToolkit,a large published library of open source software and user manuals thatare used to process and display a wide range of physiological signals[GOLDBERGER A L, Amaral L A N, Glass L, Hausdorff J M, Ivanov P Ch, MarkR G, Mietus J E, Moody G B, Peng C K, Stanley H E. PhysioBank,PhysioToolkit, and PhysioNet: Components of a New Research Resource forComplex Physiologic Signals. Circulation 101(23):e215-e220 (2000);available from PhysioNet, M.I.T. Room E25-505A, 77 Massachusetts Avenue,Cambridge, Mass. 02139]. In one embodiment of the present invention, thecontrol unit 330 contains an analog-to-digital converter to receive suchanalog respiratory signals, and software for the analysis of thedigitized respiratory waveform resides within the control unit 330. Thatsoftware extracts turning points within the respiratory waveform, suchas end-expiration and end-inspiration, and forecasts futureturning-points, based upon the frequency with which waveforms fromprevious breaths match a partial waveform for the current breath. Thecontrol unit 330 then controls the impulse generator 310 to stimulatethe selected nerve only during a selected phase of respiration, such asall of inspiration or only the first second of inspiration, or only theexpected middle half of inspiration.

In the preferred embodiment, physiological signals in addition to thoserelated to the determination of respiratory phase are measurednon-invasively. The additional signals comprise the electrocardiogram,measured by one or more chest electrocardiographic leads; the arterialblood pressure measured non-invasively and continuously with an arterialtonometer applied to patient's wrist; and a pulse oximeter applied tothe patient's fingertip. The electrocardiographic electrodes may also beused to measure transthoracic impedance, so as to obtain a signal thatrises and falls according to the phase of respiration. A respirationsignal may also be obtained from the actual electrocardiographic signal,using computer programs available in the PhysioToolkit software librarythat was mentioned above. In embodiments of the present invention, thecontrol unit 330 contains analog-to-digital converters to receive suchanalog physiological signals, and software for the analysis of thesignal waveforms resides within the control unit 330. In particular, theheart rate is derived from the electrocardiographic signals using opensource software such as the QRS detectors and heart rate tachometersthat are available in the PhysioToolkit software library, and thesystolic, diastolic, and mean blood pressure are derived from the bloodpressure waveform using software for pulse detection that is alsoavailable in the PhysioToolkit software library.

In our experiments that were summarized above (and will be described indetail below), the location and parameters of the electrical impulsesdelivered to the vagus nerve were optimized to stimulate the release ofhormones into the circulation, at concentrations that produce bronchialsmooth muscle relaxation, and that also have little effect on heart rateor blood pressure. For bronchoconstricted patients with normal heartrates and blood pressure, those are the stimulation location andparameters of choice. However, during asthma or COPD attacks oranaphylactic shock, it is sometimes the case that a significant increaseor decrease in heart rate accompanies airway constriction. In cases ofunsafe or suboptimal heart rates, the teachings of the present inventionpermit not only prompt airway dilation, but also an improved heart rate,to enable subsequent life saving measures that otherwise would beineffective or impossible due to severe constriction or otherphysiological effects. Treatment in accordance with the presentinvention provides not only bronchodilation, but also optionallyimproved heart function for a long enough period of time thatadministered medication such as epinephrine has time to take effectbefore the patient suffocates. This is because, depending on theplacement of the impulse to the selected nerve fiber, the stimulating,blocking and/or modulating signal can also improve the heart function,by potentially elevating or decreasing heart rate. Furthermore, as anoption in the present invention, parameters of the stimulation may bemodulated by the control unit 330 to control the impulse generator 310in such a way as to temporally modulate stimulation by the magneticstimulator coil 340, in such a way as to achieve and maintain the heartrate within safe or desired limits. In that case, the parameters of thestimulation are individually raised or lowered in increments (power,frequency, etc.), and the effect as an increased, unchanged, ordecreased heart rate is stored in the memory of the control unit 330.When the heart rate changes to a value outside the specified range, thecontrol unit 330 automatically resets the parameters to values that hadbeen recorded to produce a heart rate within that range, or if no heartrate within that range has yet been achieved, it increases or decreasesparameter values in the direction that previously acquired data indicatewould change the heart rate in the direction towards a heart rate in thedesired range. Similarly, the arterial blood pressure is also recordednon-invasively in an embodiment of the invention, and as describedabove, the control unit 330 extracts the systolic, diastolic, and meanarterial blood pressure from the blood pressure waveform. The controlunit 330 will then control the impulse generator 310 in such a way as totemporally modulate nerve stimulation by the magnetic stimulator coil340, in such a way as to achieve and maintain the blood pressure withinpredetermined safe or desired limits, by the same method that wasindicated above for the heart rate. Thus, even if one does not intend totreat bronchoconstriction, embodiments of the invention described abovemay be used to achieve and maintain the heart rate and blood pressurewithin desired ranges.

If one does not anticipate problems with overheating the magneticstimulator coil 340, it may nevertheless be therapeutically advantageousto program the control unit 330 to control the impulse generator 310 insuch a way as to temporally modulate stimulation by the magneticstimulator coil 340, depending on the phase of the patient'srespiration. In patent application JP2008/081479A, entitled Vagus nervestimulation system, to Yoshihoto, a system is also described for keepingthe heart rate within safe limits. When the heart rate is too high, thatsystem stimulates a patient's vagus nerve, and when the heart rate istoo low, that system tries to achieve stabilization of the heart rate bystimulating the heart itself, rather than use different parameters tostimulate the vagus nerve. In that disclosure, vagal stimulation uses anelectrode, which is described as either a surface electrode applied tothe body surface or an electrode introduced to the vicinity of the vagusnerve via a hypodermic needle. That disclosure is unrelated to theproblem of bronchoconstriction that is addressed herein, but it doesconsider stimulation during particular phases of the respiratory cycle,for the following reason. Because the vagus nerve is near the phrenicnerve, Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants did not experience this problem in the experiments reportedbelow, so the problem may be one of a misplaced electrode. In any case,the phrenic nerve controls muscular movement of the diaphragm, soconsequently, stimulation of the phrenic nerve causes the patient tohiccup or experience irregular movement of the diaphragm, or otherwiseexperience discomfort. To minimize the effects of irregular diaphragmmovement, Yoshihoto's system is designed to stimulate the phrenic nerve(and possibly co-stimulate the vagus nerve) only during the inspirationphase of the respiratory cycle and not during expiration. Furthermore,the system is designed to gradually increase and then decrease themagnitude of the electrical stimulation during inspiration (notablyamplitude and stimulus rate) so as to make stimulation of the phrenicnerve and diaphragm gradual. Patent application publicationUS2009/0177252, entitled Synchronization of vagus nerve stimulation withthe cardiac cycle of a patient, to Arthur D. Craig, discloses a methodof treating a medical condition in which the vagus nerve is stimulatedduring a portion of the cardiac cycle and the respiratory cycle. Thatdisclosure pertains to the treatment of a generic medical condition, soit is not specifically directed to the treatment of bronchoconstriction.In the present application, stimulation of selected nerve fibers duringparticular phases of respiration for the treatment ofbronchoconstriction may be motivated by two physiologicalconsiderations. The first is that contraction of bronchial smooth muscleappears to be intrinsically rhythmic. It has been reported thatbronchial smooth muscle contracts over two phases, duringmid-inspiration and early expiration. When the vagus efferent nerves arerepetitively stimulated with electric pulses, the bronchus constrictedperiodically; tonic constriction is almost absent in the bronchus inresponse to the vagally mediated descending commands. [KONDO, Tetsuri,Ichiro Kobayashi, Naoki Hayama, Gen Tazaki, and Yasuyo Ohta.Respiratory-related bronchial rhythmic constrictions in the dog withextracorporeal circulation. J Appl Physiol 88: 2031-2036, 2000].Accordingly, a rationale for stimulating the vagus nerve duringparticular phases of the respiratory cycle is that such stimulation maybe used to counteract or inhibit the constriction that occurs naturallyduring those specific phases of respiration. If the counteracting orinhibiting effects occur only after a delay, then the timing of thestimulation pulses should precede the phases of respiration during whichthe contraction would occur, by an interval corresponding to the delay.A second motivation for stimulating the vagus nerve during particularphases of respiration is that an increase or decrease in the duration ofsubsequent phases of respiration may be produced by applying thestimulation during particular phases of respiration [M. SAMMON, J. R.Romaniuk and E. N. Bruce. Bifurcations of the respiratory patternproduced with phasic vagal stimulation in the rat. J Appl Physiol 75:912-926, 1993]. In particular, a narrow window may exist at theexpiratory-inspiratory transition in which it may be possible to inducebursts of inspiratory activity followed by a prolonged breath.Accordingly, if it is therapeutically beneficial to induce deep breaths,those breaths might be induced by stimulating during that time-window.In fact, the physiologically meaningful cycle of stimulation in thiscase is not a single respiratory cycle, but is instead a collectivesequence of respiratory cycles, wherein it makes sense only to speak ofstimulation during particular parts of the sequence.

In some embodiments of the invention, it may also be therapeuticallyadvantageous to program the control unit 330 to control the impulsegenerator 310 in such a way as to modulate stimulation by the magneticstimulator coil 340, by modulating the parameters and properties of theapplied impulses, depending on the values of frequently measurednon-invasive indicators of the magnitude of bronchoconstriction. Becauseof patient motion, e.g., due to the patient's fidgeting restlessness orcontraction of the sternocleidomastoid muscle, there will inevitably besome motion of the magnetic stimulator coil 340 relative to the locationof the nerve fibers that are selected for stimulation, no matter howrigidly the coil 340 and conducting container 350 are comfortably heldagainst the patient, using a frame and strap similar to those used fortranscranial magnetic stimulation. Therefore, the power of the energyimpulse delivered to the selected nerve fibers would fluctuate or driftas a function of the fluctuating or drifting distance and angles betweenthe coil and nerve fiber, unless a method is employed to automaticallyadjust the power of the energy impulse for such fluctuations or drift.In the preferred embodiment, that method makes the adjustment bymeasuring a surrogate for FEV₁ and then adjusting the power in such away that the value of the surrogate measurement does not decreaserelative to the surrogate's previous value averaged over a predeterminednumber of prior cycles of respiration. It is understood that the poweradjustment may also occur throughout a single respiratory cycle,particularly when there is movement due to changing accessory muscleuse. Thus, in one embodiment of the present invention, the control unit330 contains an analog-to-digital converter to receive an analog signalthat is a surrogate for FEV₁, or it contains a digital interface toreceive a digital signal that is a surrogate for FEV₁, and software forthe analysis of the digitized FEV₁ surrogate data resides within thecontrol unit 330. The control unit 330 then sets parameters of theimpulse generation (such as power) to control the impulse generator 310so as to maintain or move the surrogate FEV₁ value to within a desiredrange, using the same method that was described above for the heart rateand blood pressure. It should be noted also that the patient him/herselfmay sense an improvement in breathing even before there is a clearimprovement in FEV₁ or its surrogates, in which case, verbalcommunication between patient and medical provider may be used forfeedback. Accordingly, it is understood that the medical provider mayoverride the automatic feedback and use the verbal feedback of thepatient to manually adjust stimulation parameters.

Three types of non-invasive measurements are currently recognized asbeing surrogates for the measurement of FEV₁: pulsus paradoxus,accessory muscle use, and airway resistance. In the preferredembodiment, pulsus paraduxus is measured, which is based on theobservation that in asthmatic patients (as well as other patientsexperiencing bronchoconstriction), the patient's blood pressure waveformwill rise and fall as a function of the phase of respiration. In thepreferred embodiment, the blood pressure waveform (and the magnitude ofany accompanying pulsus paradoxus) is measured non-invasively with anarterial tonometer, that is placed, for example, on the patient's wrist[James RAYNER, Flor Trespalacios, Jason Machan, Vijaya Potluri, GeorgeBrown, Linda M. Quattrucci, and Gregory D. Jay. Continuous NoninvasiveMeasurement of Pulsus Paradoxus Complements Medical Decision Making inAssessment of Acute Asthma Severity. CHEST 2006; 130:754-765].Digitization and analysis of the blood pressure waveform may beperformed in a computer dedicated to that purpose, in which case, thenumerical value of the continuously varying pulsus paradoxus signalwould be transferred to the control unit 330 through a digital interfaceconnecting the control unit 330 and dedicated computer. Alternatively,the control unit 330 may contain an analog-to-digital converter toreceive the analog tonometric signal, and the analysis of the bloodpressure waveform would be performed within the control unit 330.Instead of using an arterial tonometer to measure the blood pressurewave form and any accompanying pulsus paradoxus, it is also possible touse a pulse oximeter, attached for example, to the patient's finger tip[Donald H ARNOLD, Cathy A Jenkins, Tina V Hartert. Noninvasiveassessment of asthma severity using pulse oximeter plethysmographestimate of pulsus paradoxus physiology. BMC Pulmonary Medicine 2010,10:17; U.S. Pat. No. 7,044,917 and U.S. Pat. No. 6,869,402, entitledMethod and apparatus for measuring pulsus paradoxus, to Arnold]. Adedicated computer may be used to acquire and analyze the blood pressurewaveform and the magnitude of pulsus paradoxus, which would betransferred to the control unit 330 as indicated above for thetonometrically acquired signal, or the analog pulse oximetry signal maybe digitized and processed within the control unit 330, as indicatedabove.

Accessory muscle use may also be used as a surrogate for the measurementof FEV₁ [ARNOLD D H, Gebretsadik T, Minton P A, Higgins S, Hartert T V:Clinical measures associated with FEV1 in persons with asthma requiringhospital admission. Am J Emerg Med 2007, 25:425-429]. The accessorymuscles are not used during restful, tidal breathing of a normalpatient, but are used during labored breathing. The sternocleidomastoidmuscles are the most important accessory muscles of inspiration. Theyrun from the mastoid processes to insert along the medial third of theclavicle. To measure their use, a standard electromyogram may beperformed, the signal from which may be digitized and transferred to thecontrol unit 330 as indicated above. [T. DE MAYO, R. Miralles, D.Barrero, A. Bulboa, D. Carvajal, S. Valenzuela, and G. Ormeno. Breathingtype and body position effects on sternocleidomastoid and suprahyoid EMGactivity. Journal of Oral Rehabilitation, Volume 32, Issue 7, pages487-494, July 2005; Roberto MERLETTI, Alberto Botter, Amedeo Troiano,Enrico Merlo, Marco Alessandro Minetto. Technology and instrumentationfor detection and conditioning of the surface electromyographic signal:State of the art. Clinical Biomechanics 24 (2009) 122-134].Alternatively, non-invasive plethysmography may be used to measureaccessory muscle use, because as ventilatory demands increase, thesemuscles contract to lift the sternum and increase the anteroposteriordiameter of the upper rib cage during inspiration. The anteroposteriordiameter may be measured, for example, by respiratory inductanceplethysmography (RIP) and electrical impedance tomography (EIT). RIPuses elastic bands around the chest (and abdomen) to assess changes inlung volume. EIT measures regional impedance changes with electrodesaround the patient's chest, each of them injecting and receiving smallcurrents. Such impedance changes have been correlated with dimensionalchanges of the lung. The plethysmography signal may be digitized andtransferred to the control unit 330 as indicated above, as a measure ofthe extent to which rib cage geometry is changing as the result ofaccessory muscle use.

Another surrogate for the measurement of FEV₁ is the measurement ofairway resistance [P. D. BRIDGE, H. Lee, M. Silverman. A portable devicebased on the interrupter technique to measure bronchodilator response inschoolchildren. Eur Respir J, 1996, 9, 1368-1373]. Airway resistance isdefined as the ratio of the difference between mean alveolar pressureand airway opening pressure to flow measured at the mouth, and it may bemeasured using devices that are commercially available [e.g., MicroRint,Catalog No. MR5000 from Micromedical Ltd. and Cardinal Health UK 232Ltd, The Crescent, Jays Close, Basingstoke, RG22 4BS, U.K.]. Suchdevices have a serial or USB port that permits the control unit 330 toinstruct the device to perform the airway resistance measurement andreceive the airway resistance data in return, via a serial or USB portin the control unit 330. Because the measurement is intermittent ratherthan continuous, and because it prefers the patient to breathe passivelythrough a mouthpiece or face mask, this surrogate for the measurement ofFEV1 is not the preferred one.

FIG. 2 illustrates an exemplary electrical voltage/current profile for astimulating, blocking and/or modulating impulse applied to a portion orportions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively induced within the patient by themagnetic stimulator. As shown, a suitable electrical voltage/currentprofile 400 for the blocking and/or modulating impulse 410 to theportion or portions of a nerve may be achieved using pulse generator310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the electrode(s) 340 that deliver the stimulating, blockingand/or modulating impulse 410 to the nerve. Nerve modulating device 300may be externally powered and/or recharged may have its own power source320. By way of example, device 300 may be purchased commercially.

The parameters of the modulation signal 400 are preferably programmable,such as the frequency, amplitude, duty cycle, pulse width, pulse shape,etc. An external communication device may modify the pulse generatorprogramming to improve treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the magneticstimulator coil, the device disclosed in U.S. Patent Publication No.:2005/0216062 (the entire disclosure of which is incorporated herein byreference), may be employed. U.S. Patent Publication No.: 2005/0216062discloses a multifunctional electrical stimulation (ES) system adaptedto yield output signals for effecting electromagnetic or other forms ofelectrical stimulation for a broad spectrum of different biological andbiomedical applications, including magnetic stimulators, which produce ahigh intensity magnetic field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape such as a sine, a square or a saw-tooth wave, orsimple or complex pulse, the parameters of which are adjustable inregard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by Liboff [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type he wishes and the user can then observe theeffect of this signal on a substance being treated. As described above,one aspect of the present invention is that such feedback is provided bynon-invasive sensors producing signals that may act as surrogates forthe measurement of FEV₁.

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient. In fact, the absence ofsignificant fluctuation in naturally occurring physiological signalsfrom a patient is ordinarily considered to be an indication that thepatient is in ill health. This is because a pathological control systemthat regulates the patient's physiological variables may have becometrapped around only one of two or more possible steady states and istherefore unable to respond normally to external and internal stresses.Accordingly, even if feedback is not used to generate the modulationsignal 400, it may be useful to artificially modulate the signal in anaperiodic fashion, in such a way as to simulate fluctuations that wouldoccur naturally in a healthy individual. Thus, the noisy modulation ofthe stimulation signal may cause a pathological physiological controlsystem to be reset or undergo a non-linear phase transition, through amechanism known as stochastic resonance. In normal respiratoryphysiology, sighing at irregular intervals is thought to bring aboutsuch a resetting of the respiratory control system. Experimentally,noisy artificial ventilation may increase respiration [B. SUKI, A.Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade, E.P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41]. So, inone embodiment of the present invention, the modulation signal 400, withor without feedback, will stimulate the selected nerve fibers in such away that one or more of the stimulation parameters (power, frequency,and others mentioned herein) are varied by sampling a statisticaldistribution having a mean corresponding to a selected, or to a mostrecent running-averaged value of the parameter, and then setting thevalue of the parameter to the randomly sampled value. The sampledstatistical distributions will comprise Gaussian and 1/f, obtained fromrecorded naturally occurring random time series or by calculatedformula. Parameter values will be so changed periodically, or at timeintervals that are themselves selected randomly by sampling anotherstatistical distribution, having a selected mean and coefficient ofvariation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

The stimulation device 300, magnetic stimulation coil 340, andelectrically conducting container 350 are preferably selected andconfigured to induce a peak pulse voltage in the range from about 0.2volts to about 20 volts, at or between points in close proximity to thenerve fibers that are being stimulated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namelystimulating, blocking and/or modulating some or all of the transmissionof the selected nerve. For example the frequency may be about 1 Hz orgreater, such as between about 15 Hz to 50 Hz, more preferably around 25Hz. The modulation signal may have a pulse width selected to influencethe therapeutic result, such as about 20 microseconds or greater, suchas about 20 microseconds to about 1000 microseconds. The modulationsignal may have a peak voltage amplitude selected to influence thetherapeutic result, such as about 0.2 volts or greater, such as about0.2 volts to about 20 volts.

In a preferred embodiment of the invention, a method of treatingbronchial constriction comprises applying one or more electricalimpulse(s) of a frequency of about 15 Hz to 50 Hz to a selected regionof the vagus nerve to reduce a magnitude of constriction of bronchialsmooth muscle. As discussed in more detail below, applicant has made theunexpected discovered that applying an electrical impulse to a selectedregion of the vagus nerve within this particular frequency range resultsin almost immediate and significant improvement in bronchodilation, asdiscussed in further detail below. Applicant has further discovered thatapplying electrical impulses outside of the selected frequency range (15Hz to 50 Hz) does not result in immediate and significant improvement inbronchodilation. Preferably, the frequency is about 25 Hz. In thisembodiment, the induced electrical impulse(s) are of an amplitude ofbetween about 0.75 to 12 volts and have a pulsed on-time of betweenabout 50 to 500 microseconds, preferably about 200-400 microseconds.

In accordance with another embodiment, devices in accordance with thepresent invention are provided in a “pacemaker” type form, in whichelectrical impulses 410 are generated to a selected region of the nerveby device 300 on an intermittent basis to create in the patient a lowerreactivity of the nerve to upregulation signals.

In an alternate embodiment, a mechanical vibrator transmits energy to anerve, rather than a magnetic stimulator. In 1932, Hill demonstratedthat the human vagus nerve in the neck may be excited in someindividuals by purely mechanical means [Ian G. W. HILL. Stimulation ofthe vagus nerve and carotid sinus in man. Experimental Physiology (1932)22, 79-93]. That demonstration took place during invasive surgicalinterventions, and the mechanical stimulation involved only manualpercussion pressure. His investigations were motivated by the fact thatthe vagus nerve may be stimulated by carotid massage on the neck nearthe carotid body (as well as by Valsalva maneuver, ocular pressure,digital rectal massage, and head-up tilting), which is performed inorder to investigate causes of syncope or to treat supraventriculartachycardia. Cardioinhibitory responses may result from the massage(decreased heart rate and heart contractility, due to enhancedparasympathetic tone), as well as a drop in blood pressure (due tovasodilation of blood vessels in the legs, probably due to a decrease insympathetic nervous system tone). Although carotid massage is known todilate blood vessels in the legs, it is not known to do so in thebronchi and is therefore not used to produce bronchodiation. Subsequentinvestigators demonstrated that the vagus nerve may be stimulatedmechanically at a location where it leaves the brainstem [VladimirSHUSTERMAN, Peter J. Jannetta, Benhur Aysin, Anna Beigel, MaksimGlukhovskoy, and Irmute Usiene. Direct Mechanical Stimulation ofBrainstem Modulates Cardiac Rhythm and Repolarization in Humans. Journalof Electrocardiology Vol. 35 Supplement 2002, pp. 247-256]. Thatmechanical stimulation also took place during invasive surgery, and thestimulation occurred at 1 to 2 Hertz with a duration of 1 minute.Afferent nerves carried by the auricular branch of the vagus nerve (alsoknown as Arnold nerve and Alderman's nerve) also innervate the externalauditory meatus. When mechanically stimulated, in some individuals theymay elicit the Arnold's ear-cough reflex that is similar to a reflexthat may be elicited by stimulating other branches of the vagus nerve.[TEKDEMIR I, Aslan A, Elhan A. A clinico-anatomic study of the auricularbranch of the vagus nerve and Arnold's ear-cough reflex. Surg RadiolAnat 1998; 20:253-257].

Non-invasive mechanical stimulation of the vagus nerve at the ear isdisclosed in patent application US2008/0249439, entitled Treatment ofInflammation by Non-Invasive Stimulation, to Tracey et al., which isdirected to stimulating a subject's inflammatory reflex in a manner thatsignificantly reduces proinflammatory cytokines in the subject. Toachieve that effect, Tracey et al. disclosed that an effectivemechanical stimulation frequency is between about 50 and 500 Hz. Theyclaim their method for treatment of a long list of diseases, includingallergy, anaphylactic shock, bronchitis, emphysema, and adultrespiratory distress syndrome. However, they make no mention ofbronchial constriction or bronchodilation. They also say that the effectthat their method has on smooth muscle cells (among many other celltypes in a list) is to modulate their production of proinflammatorycytokines, but their application makes no mention of their methodmodulating the contractile properties of smooth muscle cells. Thus, ifthe non-invasive method that they disclose is useful for the treatmentof asthma, anaphylactic shock, or chronic obstructive pulmonary disease,there is no motivation or suggestion that such usefulness would berelated to relaxation of the bronchial smooth muscle. In fact, in areview article concerning the inflammatory reflex [Kevin J. TRACEY. Theinflammatory reflex. NATURE Vol. 420 (19/26 Dec. 2002) 853-859], theauthor of the review article and co-applicant for patent applicationUS2008/0249439, Kevin J. Tracey, makes no mention ofbronchoconstriction, and he only refers to smooth muscle implicitly inreference to the smooth muscle of arterioles, when he states thatstimulation of the vagus nerve to dilate arterioles is distinct fromstimulation of the vagus nerve to inhibit the inflammatory reflex. Thus,in that review, Tracey writes (p. 585): “Stimulation of efferent vagusnerve activity has been associated classically with slowing heart rate,induction of gastric motility, dilation of arterioles and constrictionof pupils. Inhibition of the inflammatory response can now be added tothis list.”

U.S. Pat. No. 4,966,164, entitled Combined sound generating device andelectrical acupuncture device and method for using the same, to Colsenet al., discloses sound/electroacupuncture that also stimulates the earmechanically, using a buzzer operating in the range of 0.5 to 20 Hz.However, the buzzer is provided in order to provide auditorystimulation, rather than the stimulation of acupuncture meridian points.Furthermore, the disclosure by Colsen et al. does not mention use oftheir invention to treat bronchoconstriction. Of note is the fact thatU.S. Pat. No. 4,966,164 discloses stimulation in the ear with mechanicalfrequencies in the range 0.5 to 20 Hz, and the aforementionedapplication US2008/0249439 discloses stimulation in the ear withmechanical frequencies in range of between 50 and 500 Hz, but neitherdiscloses the use of mechanical vibrations in the intervening range ofgreater than 20 Hz and less than 50 Hz.

FIG. 3 illustrates an alternate embodiment of the invention, in which amechanical vibrator transmits energy to a nerve. The figure contains aschematic diagram of a nerve modulating device 500 for deliveringimpulses of mechanical energy to nerves for the treatment of bronchialconstriction or hypotension associated with anaphylactic shock, COPD orasthma. As shown, device 500 may include an impulse generator 510; apower source 520 coupled to the impulse generator 510; a control unit530 in communication with the impulse generator 510 and coupled to thepower source 520; and a linear actuator 540 coupled via wires to theimpulse generator coil 510. The control unit 530 may control the impulsegenerator 510 for generation of a signal suitable for amelioration ofthe bronchial constriction or hypotension, when mechanical vibrationsare applied to the nerve non-invasively using a linear actuator 540.

It is noted that nerve modulating device 500 may be referred to by itsfunction as a pulse generator. U.S. Patent Application Publications2005/0075701 and 2005/0075702, both to Shafer, both of which areincorporated herein by reference, relating to stimulation of neurons ofthe sympathetic nervous system to attenuate an immune response, containdescriptions of pulse generators that may be applicable to the presentinvention, when adapted to drive a mechanical vibrator.

In the preferred embodiment, mechanical vibrations are produced by alinear actuator 540 as shown in FIG. 3 [BOLDEA, I. and Nasar, S. A.Linear electric actuators and generators. IEEE Transactions on EnergyConversion. Vol. 14 Issue: 3 (September 1999): 712-717; Bill BLACK, MikeLopez, and Anthony Marcos. Basics of voice coil actuators. PowerConversion and Intelligent Motion (PCIM) July 1993: 44-46]. In alternateembodiments, vibrations that are applied to the nerve may be produced byany device that is known in the art to be capable of generatingappropriate mechanical vibration, including (but not limited to): anelectromagnet, a bimorph, a piezo crystal, an electrostatic actuator, aspeaker coil, and a rotating magnet or mass. Ultrasound may also be usedto produce vibrations at frequencies lower than ultrasonic frequencies[U.S. Pat. No. 5,903,516, entitled Acoustic force generator fordetection, imaging and information transmission using the beat signal ofmultiple intersecting sonic beams, to Greenleaf et al.; U.S. Pat. No.7,753,847, entitled Ultrasound vibrometry, to Greenleaf et al.; U.S.Pat. No. 7,699,768, entitled Device and method for non-invasive,localized neural stimulation utilizing hall effect phenomenon, toKishawi]. In some embodiments, mechanical vibration is deliverednon-invasively using devices like those that are applied to the skin toreduce pain (vibratory analgesia) [Elizabeth A. ROY, Mark Hollins,William Maixner. Reduction of TMD pain by high-frequency vibration: aspatial and temporal analysis. Pain 101 (2003) 267-274; Kevin C SMITH,Stephen L Comite, Suprina Balasubramanian, Alan Carver and Judy F Liu.Vibration anesthesia: A noninvasive method of reducing discomfort priorto dermatologic procedures. Dermatology Online Journal 10 (2): 1(2004)]. Multiple sources of vibration may also be used and applied atone or more locations on the surface of the body.

The linear actuator 540 shown in FIG. 3 comprises two separable parts: acoil holder that is PI (Π)-shaped in cross-section (544), and amagnet-holder that is E-shaped in cross-section (548). The coil holder544 is a cylinder (shown in FIG. 3 as legs of the Π in cross section)that is open on one end and typically closed on the other end. Theclosed part is shown in FIG. 3 as the middle member connecting the legsof the Π in cross section. A coil of wire 542 is wrapped around orembedded within the cylindrical part of the coil holder. The coil 542 isshown in cross section in FIG. 3 as a series of blackened circles alongboth legs of the Π. A pair of lead wires emerge from the coil 542 andthen from the coil holder 544. They are attached to the impulsegenerator 510, such that electrical current may pass into one of thelead wires, through the coil, and out the other lead wire.

Air-gaps separate the coil holder 544 from magnet-holder 548, so thatthe two parts may slide relative to one another. The outside part of themagnet holder 584 is cylindrical (shown in cross section in FIG. 3 asthe top and bottom horizontal lines of an E), and permanent magnets 546are embedded on the inside diameter of that outer cylinder, such thatthe magnets facing the coil 542 across an air gap are all of the samepolarity. In the preferred embodiment, the magnets are made ofrare-earth materials. The outer cylinder is ferromagnetic, and an innercore of ferromagnetic material is attached to it (shown in cross sectionin FIG. 3 as the middle horizontal line of an E, attached to the outercylinder of the magnet holder by the vertical line of an E). Themagnetic field generated by the permanent magnets 546 is orientedradially, and the ferromagnetic components of the magnet holder completethe magnetic circuit. A Lorentz force is generated axially on the coil(and coil holder), whenever current is passed through the coil, whichwill be proportional to the current multiplied by the magnetic fluxdensity produced by the magnets. Therefore, when the impulse generator510 produces pulses of current in the coil that alternate in sign, thecoil holder will move alternately in opposite directions along its axis,i.e., vibrate. The frequency and amplitude of that mechanical vibrationare therefore determined by the frequency and amplitude of currentpulses that are generated by the impulse generator 510.

An actuator-tip 545 is attached to the closed part of the coil holder544. The linear actuator is placed into physical contact with thesurface of the patient's body on the outer surface of the actuator-tip,which is opposite to the surface of the actuator-tip that is connectedto the coil holder. A stationary surround is used to limit the spread ofvibration across the skin, as follows: a stationary ring is attached, byan adjustable metal arm, to a table that is mechanically isolated fromthe vibratory stimulator. The heavy ring (deformable metal, covered by athermal insulator) is positioned onto the patient around the area on thesurface of the skin that is vibrated by the actuator tip, therebylimiting vibration across the skin. The shape of the actuator-tipsurface that contacts the patient need not be circular, and need noteven lie in a plane, but may instead be selected to have some othershape such as rectangular or hemi-spherical or even threaded forattachment to another piece. The actuator-tip is preferably detachableso as to accommodate different tip shapes for different applications. Inthe preferred embodiment of the invention, the actuator tip will berectangular with a dimension of approximately 5 mm by 40 mm, withrounded edges so as to press comfortably against a patient's neck abovethe vagus nerve, as now described. Consider the plane of the skin on theneck to define an X-Y axis, where the X axis is vertical and the Y axisis horizontal for a standing patient. A Z axis is perpendicular to theX-Y axis, so that if the actuator tip is straight, and the actuator ispositioned parallel to the Z axis (perpendicular to the skin of theneck), vibrations will push the skin in the Z axis, perpendicular to theplane of the skin of the neck. In another embodiment, the actuator tipis L shaped, and the actuator is positioned parallel to the X-Y axis.When the actuator tip is then pressed against the skin, it will vibratethe skin within the X-Y plane. As the actuator is rotated about thepoint of skin-tip contact, it will vibrate the skin in the direction ofthe X axis, the Y axis, and intermediate angles within the X-Y plane. Inthe preferred embodiment, vibration is in the Z axis, perpendicular tothe skin of the neck.

Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line would pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein is the preferred location for non-invasive stimulation of the vagusnerve. In the preferred embodiment, the mechanical vibrator would becentered on such a point, at the level of about the fifth to sixthcervical vertebra. For a rectangular actuator-tip, the long sides of therectangle will be placed parallel to the route of the vagus nerve in theneck. Typically, the location of the carotid sheath or jugular veins ina patient (and therefore the location of the vagus nerve) will beascertained in any manner known in the art, e.g., by feel or ultrasoundimaging.

Considering that the nerve stimulating device 300 in FIG. 1 and thenerve stimulating device 500 in FIG. 3 both control electrical currentswithin a coil of wire, their functions are analogous, except that onestimulates nerves via the pulse of a magnetic field, and the otherstimulates nerves via a pulse of vibration. Accordingly, the featuresrecited for the nerve stimulating device 300, such as its use forfeedback involving FEV₁ surrogates, control of the heart rate and bloodpressure, stimulation during selected phases of the respiratory cycle,and preferred frequency of stimulation, apply as well to the nervestimulating device 500 and will not be repeated here. The preferredparameters for each nerve stimulating device are those that produce theeffects described below in connection with the detailed description ourexperiments.

In another embodiment of the invention, a selected nerve is stimulatedby delivering to it impulses of light and/or heat energy. Becauseabsorption and scattering of light increases exponentially with depth,little irradiated light at wavelengths below 800 nm can traverse palehuman skin, which has a thickness that varies from 1 to 3 mm dependingupon location. At wavelengths above 1,400 nm, there is also almost nolight transmission because of water absorption. Therefore, infraredwavelengths are ordinarily preferred to irradiate the skin surface,which can penetrate up to about 4 to 5 millimeters. To stimulate a nervenon-invasively with light, the nerve should therefore lie very near thesurface of the skin (e.g., vagus nerve at the ear), and infrared lightis preferred. Otherwise, the nerve would have to be irradiatedinvasively, using a fiber optic probe.

The ear canal (external auditory meatus, external acoustic meatus), is atube running from the outer ear to the middle ear. The human ear canalextends from the pinna (auricula, external portion of the ear) to theeardrum and is about 26 mm in length and 7 mm in diameter. Afferentnerves carried by the auricular branch of the vagus nerve (ABVN, alsoknown as Arnold's nerve and Alderman's nerve) innervate the externalauditory meatus. Mechanical stimulation of the ABVN in some individualsmay elicit the Arnold's ear-cough reflex that is similar to a reflexthat may be elicited by stimulating other branches of the vagus nerve.[TEKDEMIR I, Asian A, Elhan A. A clinico-anatomic study of the auricularbranch of the vagus nerve and Arnold's ear-cough reflex. Surg RadiolAnat 1998; 20:253-257]. The ABVN exits the skull base via thetympanomastoid fissure (auricular fissure), approximately 4 mm superiorto the stylomastoid foramen. It divides into two branches outside thecranium, with one branch running anteriorly to the facial nerve andextending in the posterior wall of the external acoustic meatus. Indissections of human cadavers, TEKDEMIR et al. found it to bedistributed either superiorly (in 5 cadavers) or inferiorly (in 3cadavers) in the external acoustic meatus. Considering such anatomicalvariability in the location of the ABVN that exists between individuals,a device for stimulating the ABVN should be positionable with twodegrees of freedom—a variable distance of insertion within the externalauditory meatus, and a variable angle of rotation about the line ofinsertion.

Stimulation of nerves by light can be separated primarily into threemechanistic categories: photochemical, photothermal, andphotomechanical. Photochemical effects ordinarily require that a dye beinjected into tissue before applying the light. Photothermal effectsrely on the transformation of absorbed light into heat. Photomechanicaleffects rely on laser-induced pressure waves disrupting tissues. Afterconsidering these potential mechanisms, Wells et al. concluded thatdirect neural stimulation with laser light is due to photothermaleffects, at least when using infrared light sources. [Jonathon WELLS,Chris Kao, Peter Konrad, Tom Milner, Jihoon Kim, Anita Mahadevan-Jansen,and E. Duco Jansen. Biophysical Mechanisms of Transient OpticalStimulation of Peripheral Nerve. Biophysical Journal Volume 93 October2007 2567-2580.] Accordingly, is useful to consider the stimulation ofnerves by heat (thermal pulses) in conjunction with the stimulation ofnerves by light.

In U.S. Pat. No. 7,657,310, entitled Treatment of reproductive endocrinedisorders by vagus nerve stimulation, to William R. Buras, there ismention of the stimulation of the vagus nerve “by light such as alaser.” However, that patent is concerned with invasive nervestimulation and is unrelated to the treatment of bronchoconstriction. Asindicated above, non-invasive stimulation of the vagus nerve using light(or heat) might be attempted at the ear. However, stimulation at the earwith light has apparently been attempted only using laser acupuncture[Peter WHITTAKER. Laser acupuncture: past, present, and future. Lasersin Medical Science (2004) 19: 69-80], which stimulates acupuncturemeridian points, not nerves. Furthermore, those meridian points arelocated on the front and back of the outer ear flap (pinna), not withinthe external auditory meatus. Those laser acupuncture applications weresuccessful when directed to the treatment of pain, smoking cessation,and weight loss, but as indicated above, acupuncture (including laseracupuncture) is not considered to be effective for the treatment ofasthma or other disorders associated with bronchoconstriction.

FIG. 4 is a schematic diagram of a nerve modulating device 800 fordelivering impulses of light and/or heat energy to nerves for thetreatment of bronchial constriction or hypotension associated withanaphylactic shock, COPD or asthma. As shown, device 800 may include animpulse generator 810; a power source 820 coupled to the impulsegenerator 810; and a control unit 830 in communication with the impulsegenerator 810 and coupled to the power source 820. The impulse generator810 is connected to a light modulator 850 that attenuates the maximumintensity of a beam of light that is produced by a light source, suchthat the intensity of light exiting the light modulator 850 tracks themagnitude of the electrical signals that are produced by the impulsegenerator 810. The light emerging from the light modulator 850 isdirected non-invasively to a selected surface of the external auditorymeatus of a patient, via an optical fiber 854 that is inserted into thelight-emitting earplug 860 at its entrance port 862. The earplug 860 maybe rotated about the optical fiber 854 at the entrance port 862, so thatlight reflected by a mirror 864 may pass through a window 866 at avariable angle of rotation about the line of earplug insertion. Theearplug 860 has an outer diameter that is selected to fit snugly withinthe patient's ear canal and is constructed from a material selected forits flexibility, biocompatability, and ease of insertion and rotation,such as polytetrafluoroethylene. However, the terminal end of theearplug 868 may be constructed from soft rubber to protect the eardrumfrom inadvertent over-insertion of the earplug.

The light source may be any appropriate source of light havingwavelengths in the range 10-8 meters to 10-3 meters, inclusive,including (but not limited to): a laser, an incandescent bulb, an arclamp, a fluorescent lamp, a light-emitting diode (LED), asuper-luminescent diode (SLD), a laser diode (LD), a cathodoluminescentphosphor that is excited by an electron beam, a light source such as afluorescent dye that is excited by another light source, or a mixture ofsuch light sources (e.g., cluster probe). In the preferred embodiment,shown in FIG. 4, the light source is a laser 840. In particular, thepreferred light source is a laser that emits light in the infraredregion of the electromagnetic spectrum, such as a gallium aluminumarsenide laser (wavelength 830 nm) or a gallium arsenide laser(wavelength 904 nm).

The light modulator 850 may be any appropriate device for temporallyattenuating the intensity of light that impinges on the light modulator,including (but not limited to): a movable variable neutral densityfilter, a mechanical light chopper wheel, a deformable membrane-mirror,an acousto-optic light modulator (Bragg cell), an electro-optic lightmodulator such as a Pockels cell, a ferroelectric liquid crystal lightmodulator, a magneto-optic light modulator, a multiple quantum welllight modulator, rotating crossed polarizers, and a vibrating mirror,diffraction grating, or hologram. It is also understood that the lightsource itself may be rapidly switched on and off or modulated in itssupplied power, in which case the light source and light modulator840/850 would be combined into a single light modulator and light-sourcedevice. The light modulator may attenuate all rays of the impinginglight by the same amount, or the light modulator may selectivelyattenuate some rays of the impinging light so as to shape the beam, aswell as to temporally modulate the intensity of the impinging light.

For the low-frequency applications described herein (less thanapproximately 500 Hz), the light modulator 850 may consist of aninternally blackened (light-absorbing) box with a light-entrance port,to which one end of optical fiber 844 is attached; a light-exit port, towhich one end of another optical fiber 854 is attached; and within thebox, a positionable, linear variable neutral density filter (e.g.,Reynard Corp., 1020 Calle Sombra, San Clemente, Calif., USA 92673, ModelR0221Q-10, with useable wavelength range from 200 nm to 2600 nm) havinga position (i.e., neutral density) that is controlled by the impulsegenerator 810. For example, the linear variable neutral density filtermay be attached to the tip of a linear actuator like the one shown inFIG. 3, except that in the present application, the actuator is attachedto the edge of the variable neutral density filter, rather than beingapplied to a patient. It is understood that if the light beam has awidth that would cover multiple densities of the variable neutraldensity filter, then the light beam may first be focused with a lensonto a single point of the filter, then collected behind the filterusing another lens.

In this embodiment, light passes from the laser 840 through the opticalfiber 844 and then enters the modulator box 850 at its entrance port.When the filter is moved to its open position by the actuator, the lightis essentially unattenuated by the filter, so that a fixed lens canfocus a maximum intensity of light onto the end of optical fiber 854 atthe light-exit port of the light modulator. When the filter is moved toa closed position by the actuator, light emerging from the optical fiber844 at the entrance port is attenuated in such a way that essentially nolight enters the optical fiber 854. As the actuator moves the variableneutral density filter continuously from the open position to the closedposition, the intensity of light entering the optical fiber 854 variesfrom a maximum to a minimum, depending on the position of the variableneutral density filter, which is controlled by the actuator, which is inturn controlled by the impulse generator 810, which is in turncontrolled by the control unit 830. Thus, by controlling the position ofthe filter within the light modulator, the control unit 830 may controlthe intensity of the light that enters the optical fiber 854, therebycontrolling the intensity of light entering the light-emitting earplug860 at its entrance port 862. It is understood in the art that insteadof using a linear actuator, one could use a rotary motor in conjunctionwith a mirror or a circular variable neutral density filter that ismounted on the rotary motor shaft, wherein the angle of the motor shaftis controlled by an impulse generator; or one could use other lightmodulating methods that were mentioned above. It is also understood thatwhen the light entering the earplug is blocked by the light modulator850, infrared light may be collected from the surface of the externalauditory meatus by the mirror 864 and optical fiber 862. In oneembodiment of the invention, a beam-splitter is interposed between theoptical fiber 862 and light modulator 850 so that light (black-bodyradiation) passing backwards from the ear and through the optical fiber862 is reflected into an infrared-sensing thermometer [U.S. Pat. No.6,272,375, entitled Mid infrared transmitting fiber optic based otoscopefor non contact tympanic membrane thermometry, to Katzir et al.; U.S.Pat. No. 5,167,235, entitled Fiber optic ear thermometer, to Seacord etal.; U.S. Pat. No. 5,381,796, entitled Ear thermometer radiationdetector, to Francesco Pompei; U.S. Pat. No. 5,790,586, entitled Methodand apparatus for simultaneously illuminating, viewing and measuring thetemperature of a body, to Hilton, Jr. et al.]. When such a thermometeris present, over-irradiation of the external auditory meatus may beprevented by sending an auditory meatus-temperature signal to thecontrol unit 830. In that case, the control unit 830 would attenuate thelight by controlling the light modulator 850 so as to keep thetemperature within a specified safe range. The control unit 830 may alsoallow light to pass only during selected phases of the respiratorycycle, so that during other phases of respiration, excess heat may betransported from the area of light stimulation by blood vessels of theear. In another embodiment, a tube is inserted into the earplug alongits side-wall to inject air that cools the external auditory meatus atthe window 866, with another tube inserted into the earplug near theentrance port 862 to carry or suck return air from earplug chamber. Theair can be injected so as to maintain constant air pressure within theearplug; or the air pressure can also pulsate, so as to providemechanical stimulation to the external auditory meatus at the window855, becoming another embodiment of the mechanical nerve stimulationthat was disclosed above.

The control unit 830 may control the impulse generator 810 forgeneration of a signal suitable for amelioration of the bronchialconstriction or hypotension when the signal is applied to the nervenon-invasively via the light-emitting earplug 860. It is noted thatnerve modulating device 800 may be referred to by its function as apulse generator. U.S. Patent Application

Publications 2005/0075701 and 2005/0075702, both to Shafer, both ofwhich are incorporated herein by reference, relating to stimulation ofneurons of the sympathetic nervous system to attenuate an immuneresponse, contain descriptions of pulse generators that may beapplicable to the present invention, when adapted for use with anoptical modulator.

Considering that the nerve stimulating device 300 in FIG. 1 controlselectrical currents within a coil of wire, and as described in theembodiment above concerning use of a linear actuator to control movementof a variable light filter, the nerve stimulating device 800 in FIG. 4also controls electrical currents within a coil of wire in the actuator,their functions are analogous, except that one stimulates nerves via thepulse of a magnetic field, and the other stimulates nerves via a pulseof light. Accordingly, the features recited for the nerve stimulatingdevice 300, such as its use for feedback involving FEV₁ surrogates,control of the heart rate and blood pressure, stimulation duringselected phases of the respiratory cycle, and preferred frequency ofstimulation, apply as well to the nerve stimulating device 800 and willnot be repeated here. The preferred parameters for each nervestimulating device are those that produce the effects described below inconnection with the detailed description our experiments.

In yet another embodiment of the invention, electrodes applied to thesurface of the neck, or to some other surface of the body, are used tonon-invasively deliver electrical energy to a nerve, instead ofdelivering the energy to the nerve via a magnetic coil, mechanicalvibrations and/or pulses of light. In particular, the vagus nerve may bebeen stimulated non-invasively using electrodes applied via leads to thesurface of the skin. For example, U.S. Pat. No. 7,340,299, entitledMethods of indirectly stimulating the vagus nerve to achieve controlledasystole, to John D. Puskas, discloses the stimulation of the vagusnerve using electrodes placed on the neck of the patient, but thatpatent is unrelated to the treatment of bronchoconstriction.Non-invasive electrical stimulation of the vagus nerve has also beendescribed in Japanese patent application JP2009233024A with a filingdate of Mar. 26, 2008, entitled Vagus Nerve Stimulation System, to FukuiYoshihito, in which a body surface electrode is applied to the neck tostimulate the vagus nerve electrically. However, that applicationpertains to the control of heart rate and is unrelated to the treatmentof bronchoconstriction.

Patent application US2010/0057154, entitled Device and Method for theTransdermal Stimulation of a Nerve of the Human Body, to Dietrich etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCall, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to Kim et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to Colsen et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to Libbus et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimulator for alpha-wave derivation, to Chung et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to Amurthur et al., also discloses electricalstimulation of the vagus nerve at the ear. However, none of thedisclosures in these patents or patent applications for electricalstimulation of the vagus nerve at the ear are used to treatbronchoconstriction.

The present embodiment of the invention uses some of the methods anddevices for delivery of electrical energy to nerves via electrodes thatwere previously disclosed in the commonly assigned co-pending U.S.patent application Ser. No. 12/422,483, entitled Percutaneous ElectricalTreatment of Tissue, which is hereby incorporated by reference in itsentirety. FIG. 1 of that application illustrates a nerve stimulatingdevice that functions in a manner that is analogous to the nervestimulating device shown in FIG. 1 of the present invention, except thatelectrical energy is applied to electrodes rather than to a coil.

In the present embodiment of the invention, a nerve stimulating devicedelivers electrical impulses to nerves. The device may include anelectrical impulse generator; a power source coupled to the electricalimpulse generator; a control unit in communication with the electricalimpulse generator and coupled to the power source; and an electrodeassembly coupled to the electrical impulse generator for attachment vialead to one or more selected regions of the patient's body. The controlunit may control the electrical impulse generator for generation of asignal suitable for amelioration of a patient's condition when thesignal is applied via the electrode assembly to the nerve. It is notedthat the nerve modulating device may be referred to by its function as apulse generator. U.S. Patent Application Publications 2005/0075701 and2005/0075702, both to Shafer, both of which are incorporated herein byreference, relating to stimulation of neurons of the sympathetic nervoussystem to attenuate an immune response, contain descriptions of pulsegenerators that may be applicable to various embodiments of the presentinvention.

The present invention differs from the one disclosed in theabove-mentioned commonly assigned co-pending U.S. patent applicationSer. No. 12/408,131 because in the present invention, the electrodes ortheir corresponding leads are applied non-invasively to the surface ofthe neck of the patient, or to some other surface of the body, therebydelivering electrical energy to a nerve through the skin and throughunderlying tissue that surrounds the nerve. Accordingly, what follows isa disclosure of the configuration of the electrodes and theircorresponding leads when applied non-invasively to the surface of theskin. Preferred embodiments of other aspects of the invention are asdescribed below in connection with the experiments that were conductedby the applicant and that were disclosed in the co-pending U.S. patentapplication Ser. No. 12/408,131.

Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line would pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein is the preferred location for non-invasive stimulation of the vagusnerve. In the preferred embodiment, the electrode configuration would becentered on such a point, at the level of about the fifth to sixthcervical vertebra. Typically, the location of the carotid sheath orjugular veins in a patient (and therefore the location of the vagusnerve) will be ascertained in any manner known in the art, e.g., by feelor ultrasound imaging.

Embodiments of the present invention differ with regard to the number ofelectrodes that are used, the distance between electrodes, and whetherdisk or ring electrodes are used. In the preferred embodiment of themethod, one selects the electrode configuration for individual patients,in such a way as to optimally focus electric fields and currents ontothe selected nerve, without generating excessive currents on the surfaceof the skin. The method describing this tradeoff between focality andsurface currents is as described by DATTA et al. [Abhishek DATTA, MagedElwassif, Fortunato Battaglia and Marom Bikson. Transcranial currentstimulation focality using disc and ring electrode configurations: FEManalysis. J. Neural Eng. 5 (2008): 163-174]. The present invention usesthe electrode configurations that are listed in that publication(bipolar, tripolar, concentric ring, and double concentric ring, eachhaving multiple separations and radii), except that in our invention,elliptical ring electrodes are also used rather than just circular ringelectrodes, in which elliptical electrodes may have a major axis thatmay be as large as ten times the length of the ellipse's minor axis.When elliptical electrodes are used, the major axis of the ellipse isaligned to be parallel with the axis of the nerve that is selected forstimulation. Furthermore, the electrodes may fit the curvature ofpatient's body surface, rather than be only planar. Although DATTA etal. are addressing the selection of electrode configuration specificallyfor transcranial current stimulation, the principles that they describeare applicable to peripheral nerves as well [RATTAY F. Analysis ofmodels for extracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36(1989): 676-682].

To implement the preferred embodiment, the user endeavors to stimulatethe selected nerve with a succession of electrode configurations,beginning with the most focal configuration (e.g., the one with thehighest value of mDESCD/CSCD in Table 1 of the article by DATTA et al.).For the initial configuration, the electrodes are centered on thepatient's neck at the above-mentioned preferred location, and themaximum pulse current is slowly increased until the patient first feelsan uncomfortable sensation at the surface of the skin. The maximum pulsecurrent is then reduced by about 5 percent, and after about ten minutesof stimulation, the effect of the stimulation is ascertained bymeasuring the patient's FEV₁ or any of its surrogate measurements thatwere described above. If stimulation with that electrode configurationis not successful in significantly increasing the patient's FEV₁, theelectrode configuration is replaced with one that is less focal (e.g.,the one with second to the highest value of mDESCD/CSCD in Table 1 ofthe article by DATTA et al.). Again, the maximum pulse current is slowlyincreased until the patient first feels an uncomfortable sensation atthe surface of the skin; the maximum pulse current is reduced by about 5percent; and the effect of the stimulation is ascertained by measuringthe patient's FEV₁ or any of the surrogate measurements described above.If stimulation with that second electrode configuration is notsuccessful in significantly increasing the patient's FEV₁, the electrodeconfiguration is again replaced with one that is less focal (e.g., theone with third to the highest value of mDESCD/CSCD in Table 1 of thearticle by DATTA et al.). Proceeding in this manner, one may eventuallydetermine that there is an electrode configuration that produces asignificant increase in the patient's FEV₁, without generating excessivecurrents on the surface of the skin. In alternate embodiments or theinvention, the electrode configurations may be successively more focal,or the electrode configurations may be restricted to only one type (suchas concentric ring), or distances and diameters other than those listedby DATTA et al. may be used, or one may select electrode configurationsbased on previous experience with a patient.

Considering that the nerve stimulating device 300 in FIG. 1 and thenerve stimulating device described above for use with electrodes bothcontrol the shape of electrical impulses, their functions are analogous,except that one stimulates nerves via a pulse of a magnetic field, andthe other stimulates nerves via an electrical pulse applied throughsurface electrodes. Accordingly, the features recited for the nervestimulating device 300, such as its use for feedback involving FEV₁surrogates, control of the heart rate and blood pressure, stimulationduring selected phases of the respiratory cycle, and preferred frequencyof stimulation, apply as well to the latter stimulating device and willnot be repeated here. The preferred parameters for each nervestimulating device are those that produce the effects described below inconnection with the detailed description our experiments.

A general approach to treating bronchial constriction in accordance withone or more embodiments of the invention is now described, beforediscussing the details of applicant's experiments that were summarizedabove. The general approach may include a method of (or apparatus for)treating bronchial constriction associated with anaphylactic shock, COPDor asthma, comprising applying at least one impulse of energy to one ormore selected nerve fibers of a mammal in need of relief of bronchialconstriction. The method may include applying one or more stimulationsignals to produce at least one impulse of energy, wherein the one ormore stimulation signals are of a frequency between about 15 Hz to 50Hz.

The one or more stimulation signals may be of an amplitude equivalent tobetween about 1-12 joules per coulomb of displaced charged particles.The one or more stimulation signals may be one or more of a full orpartial sinusoid, square wave, rectangular wave, and/or triangle wave.The one or more stimulation signals may have a pulsed on-time of betweenabout 50 to 500 microseconds, such as about 100, 200 or 400microseconds. The polarity of the pulses may be maintained eitherpositive or negative. Alternatively, the polarity of the pulses may bepositive for some periods of the wave and negative for some otherperiods of the wave. By way of example, the polarity of the pulses maybe altered about every second.

In one particular embodiment of the present invention, impulses ofenergy are delivered to one or more portions of the vagus nerve. Thevagus nerve is composed of motor and sensory fibers. The vagus nerveleaves the cranium and is contained in the same sheath of dura matterwith the accessory nerve. The vagus nerve passes down the neck withinthe carotid sheath to the root of the neck. The branches of distributionof the vagus nerve include, among others, the superior cardiac, theinferior cardiac, the anterior bronchial and the posterior bronchialbranches. On the right side, the vagus nerve descends by the trachea tothe back of the root of the lung, where it spreads out in the posteriorpulmonary plexus. On the left side, the vagus nerve enters the thorax,crosses the left side of the arch of the aorta, and descends behind theroot of the left lung, forming the posterior pulmonary plexus.

In mammals, two vagal components have evolved in the brainstem toregulate peripheral parasympathetic functions. The dorsal vagal complex(DVC), consisting of the dorsal motor nucleus (DMNX) and itsconnections, controls parasympathetic function below the level of thediaphragm, while the ventral vagal complex (VVC), comprised of nucleusambiguus and nucleus retrofacial, controls functions above the diaphragmin organs such as the heart, thymus and lungs, as well as other glandsand tissues of the neck and upper chest, and specialized muscles such asthose of the esophageal complex.

The parasympathetic portion of the vagus innervates ganglionic neuronswhich are located in or adjacent to each target organ. The VVC appearsonly in mammals and is associated with positive as well as negativeregulation of heart rate, bronchial constriction, bronchodilation,vocalization and contraction of the facial muscles in relation toemotional states. Generally speaking, this portion of the vagus nerveregulates parasympathetic tone. The VVC inhibition is released (turnedoff) in states of alertness. This in turn causes cardiac vagal tone todecrease and airways to open, to support responses to environmentalchallenges.

The parasympathetic tone is balanced in part by sympatheticinnervations, which generally speaking supplies signals tending to relaxthe bronchial muscles so overconstriction does not occur. Overall,airway smooth muscle tone is dependent on several factors, includingparasympathetic input, inhibitory influence of circulating epinephrine,iNANC nerves and sympathetic innervations of the parasympatheticganglia. Stimulation of certain nerve fibers of the vagus nerve(upregulation of tone), such as occurs in asthma or COPD attacks oranaphylactic shock, results in airway constriction and a decrease inheart rate. In general, the pathology of severe asthma, COPD andanaphylaxis appear to be mediated by inflammatory cytokines thatoverwhelm receptors on the nerve cells and cause the cells to massivelyupregulate the parasympathetic tone.

The methods described herein of applying an impulse of energy to aselected region of the vagus nerve may further be refined such that theat least one region may comprise at least one nerve fiber emanating fromthe patient's tenth cranial nerve (the vagus nerve), and in particular,at least one of the anterior bronchial branches thereof, oralternatively at least one of the posterior bronchial branches thereof.Preferably the impulse is provided to at least one of the anteriorpulmonary or posterior pulmonary plexuses aligned along the exterior ofthe lung. As necessary, the impulse may be directed to nervesinnervating only the bronchial tree and lung tissue itself. In addition,the impulse may be directed to a region of the vagus nerve to stimulate,block and/or modulate both the cardiac and bronchial branches. Asrecognized by those having skill in the art, this embodiment should becarefully evaluated prior to use in patients known to have preexistingcardiac issues.

Experiments were performed to identify exemplary methods of how signals,such as electrical signals, can be supplied to the peripheral nervefibers that innervate and/or control the bronchial smooth muscle to (i)reduce the sensitivity of the muscle to the signals to constrict, and(ii) to blunt the intensity of, or break the constriction once it hasbeen initiated. In particular, specific signals were applied to theselected nerves in guinea pigs to produce selective stimulation,interruption or reduction in the effects of nerve activity leading toattenuation of histamine-induced bronchoconstriction.

Male guinea pigs (400 g) were transported to the lab and immediatelyanesthetized with an i.p. injection of urethane 1.5 g/kg. Skin over theanterior neck was opened and the carotid artery and both jugular veinswere cannulated with PE50 tubing to allow for blood pressure/heart ratemonitoring and drug administration, respectively. The trachea wascannulated and the animal ventilated by positive pressure, constantvolume ventilation followed by paralysis with succinylcholine (10ug/kg/min) to paralyze the chest wall musculature to remove thecontribution of chest wall rigidity from airway pressure measurements.

Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine fromnerve terminals that may interfere with the nerve stimulation. In theseexperiments, vagus nerves were exposed and connected to electrodes toallow selective stimuli of these nerves. Following 15 minutes ofstabilization, baseline hemodynamic and airway pressure measurementswere made before and after the administration of repetitive doses ofi.v. histamine.

Following the establishment of a consistent response to i.v. histamine,nerve stimulation was attempted at variations of frequency, voltage andpulse duration to identity parameters that attenuate responses to i.v.histamine. Bronchoconstriction in response to i.v. histamine is known tobe due both to direct airway smooth muscle effects and to stimulation ofvagal nerves to release acetylcholine.

At the end of vagal nerve challenges, atropine was administered i.v.before a subsequent dose of histamine to determine what percentage ofthe histamine-induced bronchoconstriction was vagal nerve induced. Thiswas considered a 100% response. Success of electrical interruption invagal nerve activity in attenuating histamine-inducedbronchoconstriction was compared to this maximum effect. Euthanasia wasaccomplished with intravenous potassium chloride.

In order to measure the bronchoconstriction, the airway pressure wasmeasured in two places. The blood pressure and heart rate were measuredto track the subjects' vital signs. In all the following graphs, the topline BP shows blood pressure, second line AP1 shows airway pressure,third line AP2 shows airway pressure on another sensor, the last line HRis the heart rate derived from the pulses in the blood pressure.

In the first animals, the signal frequency applied was varied from lessthan 1 Hz through 2,000 Hz, and the voltage was varied from 1V to 12V.Initial indications seemed to show that an appropriate signal was 1,000Hz, 400 μs, and 6-10V.

FIG. 5 graphically illustrates exemplary experimental data on guinea pig#2. More specifically, the graphs of FIG. 5 show the effect of a 1000Hz, 400 μS, 6V square wave signal applied simultaneously to both leftand right branches of the vagus nerve in guinea pig #2 when injectedwith 12 μg/kg histamine to cause airway pressure to increase. The firstpeak in airway pressure is histamine with the electric signal applied tothe vagus, the next peak is histamine alone (signal off), the third peakis histamine and signal again, fourth peak is histamine alone again. Itis clearly shown that the increase in airway pressure due to histamineis reduced in the presence of the 1000 Hz, 400 μS and 6V square wave onthe vagus nerve. The animal's condition remained stable, as seen by thefact that the blood pressure and heart rate are not affected by thiselectrical signal.

After several attempts on the same animal to continue to reproduce thiseffect with the 1,000 Hz signal, however, we observed that the abilityto continuously stimulate and suppress airway constriction wasdiminished, and then lost. It appeared that the nerve was no longerconducting. This conclusion was drawn from the facts that (i) there wassome discoloration of the nerve where the electrode had been makingcontact, and (ii) the effect could be resuscitated by moving the leaddistally to an undamaged area of the nerve, i.e. toward the organs, butnot proximally, i.e., toward the brain. The same thing occurred withanimal #3. It has been hypothesized that the effect seen was, therefore,accompanied by a damaging of the nerve, which would not be clinicallydesirable.

To resolve the issue, in the next animal (guinea pig #4), we fabricateda new set of electrodes with much wider contact area to the nerve. Withthis new electrode, we started investigating signals from 1 Hz to 3,000Hz again. This time, the most robust effectiveness and reproducibilitywas found at a frequency of 25 Hz, 400 μs, 1V.

FIG. 6 graphically illustrates exemplary experimental data on guinea pig#5. The graphs of FIG. 6 show the effect of a 25 Hz, 400 μS, 1V squarewave signal applied to both left and right vagus nerve in guinea pig #5when injected with 8 μg/kg histamine to cause airway pressure toincrease. The first peak in airway pressure is from histamine alone, thenext peak is histamine and signal applied. It is clearly shown that theincrease in airway pressure due to histamine is reduced in the presenceof the 25 Hz, 400 μS, 1V square wave on the vagus nerve.

FIG. 7 graphically illustrates additional exemplary experimental data onguinea pig #5. The graphs of FIG. 7 show the effect of a 25 Hz, 200 μS,1V square wave signal applied to both of the left and right vagus nervesin guinea pig #5 when injected with 8 μg/kg histamine to cause airwaypressure to increase. The second peak in airway pressure is fromhistamine alone, the first peak is histamine and signal applied. It isclearly shown that the increase in airway pressure due to histamine isreduced in the presence of the 25 Hz, 200 μS, 1V square wave on thevagus nerve. It is clear that the airway pressure reduction is evenbetter with the 200 μS pulse width than the 400 μS signal.

FIG. 8 graphically illustrates further exemplary experimental data onguinea pig #5. The graphs of FIG. 8 show repeatability of the effectseen in the previous graph. The animal, histamine and signal are thesame as the graphs in FIG. 7.

It is significant that the effects shown above were repeated severaltimes with this animal (guinea pig #5), without any loss of nerveactivity observed. We could move the electrodes proximally and distallyalong the vagus nerve and achieve the same effect. It was, therefore,concluded that the effect was being achieved without damaging the nerve.

FIG. 9 graphically illustrates subsequent exemplary experimental data onguinea pig #5. The graphs of FIG. 9 show the effect of a 25 Hz, 100 μS,1V square wave that switches polarity from + to − voltage every second.This signal is applied to both left and right vagus nerve in guinea pig#5 when injected with 8 μg/kg histamine to cause airway pressure toincrease. From left to right, the vertical dotted lines coincide withairway pressure events associated with: (1) histamine alone (largeairway spike—followed by a very brief manual occlusion of the airwaytube); (2) histamine with a 200 μS signal applied (smaller airwayspike); (3) a 100 μS electrical signal alone (no airway spike); (4)histamine with a 100 uS signal applied (smaller airway spike again); (5)histamine alone (large airway spike); and (6) histamine with the 100 μSsignal applied.

This evidence strongly suggests that the increase in airway pressure dueto histamine can be significantly reduced by the application of a 25 Hz,100 μS, 1V square wave with alternating polarity on the vagus nerve.

FIG. 10 graphically illustrates exemplary experimental data on guineapig #6. The graphs in FIG. 10 show the effect of a 25 Hz, 200 μS, 1Vsquare wave that switches polarity from + to − voltage every second.This signal is applied to both left and right vagus nerve in guinea pig#6 when injected with 16 μg/kg histamine to cause airway pressure toincrease. (Note that this animal demonstrated a very high tolerance tothe effects of histamine, and therefore was not an ideal test subjectfor the airway constriction effects, however, the animal did provide uswith the opportunity to test modification of other signal parameters.)

In this case, the first peak in airway pressure is from histamine alone,the next peak is histamine with the signal applied. It is clearly shownthat the increase in airway pressure due to histamine is reducedmoderately in its peak, and most definitely in its duration, when in thepresence of the 25 Hz, 200 μS, 1V square wave with alternating polarityon the vagus nerve.

FIG. 11 graphically illustrates additional exemplary experimental dataon guinea pig #6. As mentioned above, guinea pig #6 in the graphs ofFIG. 10 above needed more histamine than other guinea pigs (16-20 μg/kgvs 8 μg/kg) to achieve the desired increase in airway pressure. Also,the beneficial effects of the 1V signal were less pronounced in pig #6than in #5. Consequently, we tried increasing the voltage to 1.5V. Thefirst airway peak is from histamine alone (followed by a series ofmanual occlusions of the airway tube), and the second peak is the resultof histamine with the 1.5V, 25 Hz, 200 μS alternating polarity signal.The beneficial effects are seen with slightly more impact, but notsubstantially better than the 1V.

FIG. 12 graphically illustrates further exemplary experimental data onguinea pig #6. Since guinea pig #6 was losing its airway reaction tohistamine, we tried to determine if the 25 Hz, 200 μS, 1V, alternatingpolarity signal could mitigate the effects of a 20V, 20 Hz airwaypressure stimulating signal that has produced a simulated asthmaticresponse. The first airway peak is the 20V, 20 Hz stimulator signalapplied to increase pressure, then switched over to the 25 Hz, 200 μS,1V, alternating polarity signal. The second peak is the 20V, 20 Hzsignal alone. The first peak looks modestly lower and narrower than thesecond. The 25 Hz, 200 μS, 1V signal may have some beneficial airwaypressure reduction after electrical stimulation of airway constriction.

FIG. 13 graphically illustrates subsequent exemplary experimental data.On guinea pig #6 we also investigated the effect of the 1V, 25 Hz, and200 μS alternating polarity signal. Even after application of the signalfor 10 minutes continuously, there was no loss of nerve conduction orsigns of damage.

FIG. 14 graphically illustrates exemplary experimental data on guineapig #8. The graph below shows the effect of a 25 Hz, 200 μS, 1V squarewave that switches polarity from + to − voltage every second. Thissignal is applied to both left and right vagus nerve in guinea pig #8when injected with 12 μg/kg histamine to cause airway pressure toincrease. The first peak in airway pressure is from histamine alone, thenext peak is histamine with the signal applied. It is clearly shown thatthe increase in airway pressure due to histamine is reduced in thepresence of the 25 Hz, 200 μS, 1V square wave with alternating polarityon the vagus nerve. We have reproduced this effect multiple times, on 4different guinea pigs, on 4 different days.

The airway constriction induced by histamine in guinea pigs can besignificantly reduced by applying appropriate electrical signals to thevagus nerve. We found at least 2 separate frequency ranges that havethis effect. At 1000 Hz, 6V, 400 μS the constriction is reduced, butthere is evidence that this is too much power for the nerve to handle.This may be mitigated by different electrode lead design in futuretests. Different types of animals also may tolerate differentlydiffering power levels.

With a 25 Hz, 1V, 100-200 μS signal applied to the vagus nerve, airwayconstriction due to histamine is significantly reduced. This has beenrepeated on multiple animals many times. There is no evidence of nervedamage, and the power requirement of the generator is reduced by afactor of between 480 (40×6×2) and 960 (40×6−4) versus the 1000 Hz, 6V,400 μS signal.

In addition to the exemplary testing described above, further testing onguinea pigs was made by applicant to determine the optimal frequencyrange for reducing bronchoconstriction. These tests were all completedsimilarly as above by first establishing a consistent response to i.v.histamine, and then performing nerve stimulation at variations offrequency, voltage and pulse duration to identity parameters thatattenuate responses to i.v. histamine. The tests were conducted on over100 animals at the following frequency values: 1 Hz, 10 Hz, 15 Hz, 25Hz, 50 Hz, 250 Hz, 500 Hz, 1000 Hz, 2000 Hz and 3000 Hz at pulsedurations from 0.16 ms to 0.4 ms with most of the testing done at 0.2ms. In each of the tests, applicant attempted to achieve a decrease inthe histamine transient. Any decrease was noted, while a 50% reductionin histamine transient was considered a significant decrease.

The 25 Hz signal produced the best results by far with about 68% of theanimals tested (over 50 animals tested at this frequency) achieving areduction in histamine transient and about 17% of the animals achievinga significant (i.e., greater than 50%) reduction. In fact, 25 Hz was theonly frequency in which any animal achieved a significant decrease inthe histamine transient. About 30% of the animals produced no effect andonly 2% (one animal) resulted in an increase in the histamine transient.

The 15 Hz signal was tested on 18 animals and showed some positiveeffects, although not as strong as the 25 Hz signal. Seven of theanimals (39%) demonstrated a small decrease in histamine transient andnone of the animals demonstrated an increase in histamine transient.Also, none of the animals achieved a significant (greater than 50%)reduction as was seen with the 25 Hz signal.

Frequency ranges below 15 Hz had little to no effect on the histaminetransient, except that a 1 Hz signal had the opposite effect on oneanimal (histamine transient actually increased indicating a furtherconstriction of the bronchial passages). Frequency ranges at or above 50Hz appeared to either have no effect or they increased the histaminetransient and thus increased the bronchoconstriction.

These tests demonstrate that applicant has made the surprising andunexpected discovery that a signal within a small frequency band willhave a clinically significant impact on reducing the magnitude ofbronchial constriction on animals subject to histamine. In particular,applicant has shown that a frequency range of about 15 Hz to about 50 Hzwill have some positive effect on counteracting the impact of histamine,thereby producing bronchodilation. Frequencies outside of this range donot appear to have any impact and, in some case, make thebronchoconstriction worse. In particular, applicant has found that thefrequency signal of 25 Hz appears to be the optimal and thus preferredfrequency as this was the only frequency tested that resulted in asignificant decrease in histamine transient in at least some of theanimals and the only frequency tested that resulted in a positiveresponse (i.e., decrease in histamine transient) in at least 66% of thetreated animals.

FIGS. 15-18 graphically illustrate exemplary experimental data obtainedon five human patients in accordance with multiple embodiments of thepresent invention. In the first patient (see FIGS. 15 and 16), a 34year-old, Hispanic male patient with a four year history of severeasthma was admitted to the emergency department with an acute asthmaattack. He reported self treatment with albuterol without success. Uponadmission, the patient was alert and calm but demonstrated bilateralwheezing, elevated blood pressure (BP) (163/92 mmHg) related to chronichypertension, acute bronchitis, and mild throat hyperemia. All othervital signs were normal. The patient was administered albuterol (2.5mg), prednisone (60 mg PO), and zithromax (500 mg PO) withoutimprovement. The spirometry assessment of the lung function revealed aForced Expiratory Volume in 1 second (FEV₁) of 2.68 l/min or 69% ofpredicted. Additional albuterol was administered without benefit and thepatient was placed on supplemental oxygen (2 l/min).

A study entailing a new investigational medical device for stimulatingthe selected nerves near the carotid sheath was discussed with thepatient and, after review, the patient completed the Informed Consent.Following a 90 minute observational period without notable improvementin symptoms, the patient underwent placement of a percutaneous, bipolarelectrode to stimulate the selected nerves (see FIG. 16). Usinganatomical landmarks and ultrasound guidance, the electrode was insertedto a position near the carotid sheath, and parallel to the vagus nerve.

The electrode insertion was uneventful and a subthreshold test confirmedthe device was functioning. Spirometry was repeated and FEV₁ remainedunchanged at 2.68 l/min. Stimulation (25 Hz, 300 microsecond pulse widthsignal) strength was gradually increased until the patient felt a mildmuscle twitch at 7.5 volts then reduced to 7 volts. This settingachieved therapeutic levels without discomfort and the patient was ableto repeat the FEV₁ test without difficulty. During stimulation, the FEV₁improved immediately to 3.18 l/min and stabilized at 3.29 l/min (85%predicted) during 180 minutes of testing. The benefit remained duringthe first thirty minutes after terminating treatment, then decreased. By60 minutes post stimulation, dyspnea returned and FEV₁ decreased to nearprestimulation levels (73% predicted) (FIG. 2). The patient remainedunder observation overnight to monitor his hypertension and thendischarged. At the 1-week follow-up visit, the exam showed completehealing of the insertion site, and the patient reported no after effectsfrom the treatment.

This was, to the inventor's knowledge, the first use of nervestimulation in a human asthma patient to treat bronchoconstriction. Inthe treatment report here, invasive surgery was not required. Instead aminimally invasive, percutaneous approach was used to position anelectrode in close proximity to the selected nerves. This was arelatively simple and rapid procedure that was performed in theemergency department and completed in approximately 10 minutes withoutevidence of bleeding or scarring.

FIG. 17 graphically illustrates another patient treated according to thepresent invention. Increasing doses of methacholine were given until adrop of 24% in FEV₁ was observed at 1 mg/ml. A second FEV₁ was takenprior to insertion of the electrode. The electrode was then inserted andanother FEV₁ taken after electrode insertion and before stimulation. Thestimulator was then turned on to 10 V for 4 minutes, the electroderemoved and a post-stimulation FEV₁ taken showing a 16% increase. Afinal rescue albuterol treatment restored normal FEV₁.

FIG. 18 is a table summarizing the results of all five human patients.In all cases, FEV₁ values were measured prior to administration of theelectrical impulse delivery to the patient according to the presentinvention. In addition, FEV₁ values were measures at every 15 minutesafter the start of treatment. A 12% increase in FEV₁ is consideredclinically significant. All five patients achieved a clinicallysignificant increase in FEV₁ of 12% or greater in 90 minutes or less,which represents a clinically significant increase in an acute period oftime. In addition, all five patients achieved at least a 19% increase inFEV₁ in 150 minutes or less.

As shown, the first patient initially presented with an FEV₁ of 61% ofpredicted. Upon application of the electrical impulse described above,the first patient achieved at least a 12% increase in FEV₁ in 15 minutesor less and achieved a peak increase in FEV₁ of 43.9% after 75 minutes.The second patient presented with an FEV₁ of 51% of predicted, achievedat least a 12% increase in FEV₁ in 30 minutes or less and achieved apeak increase in FEV₁ of 41.2% after 150 minutes. The third patientpresented with an FEV₁ of 16% of predicted, achieved at least a 12%increase in FEV₁ in 15 minutes or less and achieved a peak increase inFEV₁ of about 131.3% in about 150 minutes. However, it should be notedthat this patient's values were abnormal throughout the testing period.The patient was not under extreme duress as a value of 16% of predictedwould indicate. Therefore, the exact numbers for this patient aresuspect, although the patient's symptoms clearly improved and the FEV₁increased in any event. The fourth patient presented with an FEV₁ ofpredicted of 66%, achieved at least a 12% increase in FEV₁ in 90 minutesor less and achieved a peak increase in FEV₁ of about 19.7% in 90minutes or less. Similarly, the fifth patient presented with an FEV₁ ofpredicted of 52% and achieved a 19.2% peak increase in FEV₁ in 15minutes or less. The electrode in the fifth patient was unintentionallyremoved around 30 minutes after treatment and, therefore, a true peakincrease in FEV₁ was not determined.

In U.S. patent application Ser. No. 10/990,938 filed Nov. 17, 2004(Publication Number US2005/0125044A1), Kevin J. Tracey proposes a methodof treating many diseases including, among others, asthma, anaphylacticshock, sepsis and septic shock by electrical stimulation of the vagusnerve. However, the examples in the Tracey application use an electricalsignal that is 1 to 5V, 1 Hz and 2 mS to treat endotoxic shock, and noexamples are shown that test the proposed method on an asthma model, ananaphylactic shock model, or a sepsis model. The applicants of thepresent application performed additional testing to determine ifTracey's proposed method has any beneficial effect on asthma or bloodpressure in the model that shows efficacy with the method used in thepresent application. The applicants of the present application sought todetermine whether Tracey's signals can be applied to the vagus nerve toattenuate histamine-induced bronchoconstriction and increase in bloodpressure in guinea pigs.

Male guinea pigs (400 g) were transported to the lab and immediatelyanesthetized with an i.p. injection of urethane 1.5 g/kg. Skin over theanterior neck was opened and the carotid artery and both jugular veinsare cannulated with PE50 tubing to allow for blood pressure/heart ratemonitoring and drug administration, respectively. The trachea wascannulated and the animal ventilated by positive pressure, constantvolume ventilation followed by paralysis with succinylcholine (10ug/kg/min) to paralyze the chest wall musculature to remove thecontribution of chest wall rigidity from airway pressure measurements.

Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine fromnerve terminals that may interfere with vagal nerve stimulation. Bothvagus nerves were exposed and connected to electrodes to allow selectivestimuli of these nerves. Following 15 minutes of stabilization, baselinehemodynamic and airway pressure measurements were made before and afterthe administration of repetitive doses of i.v. histamine.

Following the establishment of a consistent response to i.v. histamine,vagal nerve stimulation was attempted at variations of 1 to 5 volts, 1Hz, 2 mS to identity parameters that attenuate responses to i.v.histamine. Bronchoconstriction in response to i.v. histamine is known tobe due to both direct airway smooth muscle effects and due tostimulation of vagal nerves to release acetylcholine.

At the end of vagal nerve challenges atropine was administered i.v.before a subsequent dose of histamine to determine what percentage ofthe histamine-induced bronchoconstriction was vagal nerve induced. Thiswas considered a 100% response. Success of electrical interruption invagal nerve activity in attenuating histamine-inducedbronchoconstriction was compared to this maximum effect. Euthanasia wasaccomplished with intravenous potassium chloride.

In order to measure the bronchoconstriction, the airway pressure wasmeasured in two places. The blood pressure and heart rate were measuredto track the subjects' vital signs.

In all the following graphs, the top line BP (red) shows blood pressure,second line AP1 shows airway pressure, third line AP2 shows airwaypressure on another sensor, the last line HR is the heart rate derivedfrom the pulses in the blood pressure.

FIG. 19 graphically illustrates exemplary experimental data from a firstexperiment on another guinea pig. The graph shows the effects ofTracey's 1V, 1 Hz, 2 mS waveform applied to both vagus nerves on theguinea pig. The first peak in airway pressure is from histamine alone,after which Tracey's signal was applied for 10 minutes as proposed inTracey's patent application. As seen from the second airway peak, thesignal has no noticeable effect on airway pressure. The animal's vitalsigns actually stabilized, seen in the rise in blood pressure, after thesignal was turned off.

FIG. 20 graphically illustrates exemplary experimental data from asecond experiment on the guinea pig in FIG. 19. The graph shows theeffects of Tracey's 1V, 1 Hz, 2 mS waveform with the polarity reversed(Tracey did not specify polarity in the patent application) applied toboth vagus nerves on the guinea pig. Again, the signal has no beneficialeffect on airway pressure. In fact, the second airway peak from thesignal and histamine combination is actually higher than the first peakof histamine alone.

FIG. 21 graphically illustrates exemplary experimental data from a thirdexperiment on the guinea pig in FIG. 19. The graph shows the effects ofTracey's 1V, 1 Hz, 2 mS waveform applied to both vagus nerves on theguinea pig. Again, the signal has no beneficial effect on airwaypressure. Instead, it increases airway pressure slightly throughout theduration of the signal application.

FIG. 22 graphically illustrates additional exemplary experimental datafrom an experiment on a subsequent guinea pig. The graph shows, fromleft to right, application of the 1.2V, 25 Hz, 0.2 mS signal disclosedin the present application, resulting in a slight decrease in airwaypressure in the absence of additional histamine. The subsequent threeelectrical stimulation treatments are 1V, 5V, and 2.5V variations ofTracey's proposed signal, applied after the effects of a histamineapplication largely had subsided. It is clear that the Tracey signals donot cause a decrease in airway pressure, but rather a slight increase,which remained and progressed over time.

FIG. 23 graphically illustrates further exemplary experimental data fromadditional experiments using signals within the range of Tracey'sproposed examples. None of the signals proposed by Tracey had anybeneficial effect on airway pressure. Factoring in a potential range ofsignals, one experiment used 0.75V, which is below Tracey's proposedrange, but there was still no beneficial effect on airway pressure.

FIG. 24 graphically illustrates exemplary experimental data fromsubsequent experiments showing the effect of Tracey's 5V, 1 Hz, 2 mSsignal, first without and then with additional histamine. It is clearthat the airway pressure increase is even greater with the signal, asthe airway pressure progressively increased during the course of signalapplication. Adding the histamine after prolonged application of theTracey signal resulted in an even greater increase in airway pressure.

The full range of the signal proposed by Tracey in his patentapplication was tested in the animal model of the present application.No reduction in airway pressure was seen. Most of the voltages resultedin detrimental increases in airway pressure and detrimental effects tovital signs, such as decreases in blood pressure.

In International Patent Application Publication Number WO 93/01862,filed Jul., 22 1992, Joachim Wernicke and Reese Terry (hereinafterreferred to as “Wernicke”) propose a method of treating respiratorydisorders such as asthma, cystic fibrosis and apnea by applying electricsignals to the patient's vagus nerve. However, Wernicke specificallyteaches to apply a signal that blocks efferent activity in the vagusnerve to decrease the activity of the vagus nerve to treat asthma.Moreover, the example disclosed in Wernicke for the treatment of asthmais an electrical impulse having a frequency of 100 Hz, a pulse width of0.5 ms, an output current of 1.5 mA and an OFF time of 10 seconds forevery 500 seconds of ON time (see Table 1 on page 17 of Wernicke). Theapplicants of the present application performed additional testing todetermine if Wernicke's proposed method has any beneficial effect onbronchodilation or blood pressure in the model that shows efficacy withthe method used in the present application. The applicants of thepresent application sought to determine whether Wernicke's signal can beapplied to the vagus nerve to attenuate histamine-inducedbronchoconstriction and increase in blood pressure in guinea pigs.

Similar to the Tracey testing, male guinea pigs (400 g) were transportedto the lab and immediately anesthetized with an i.p. injection ofurethane 1.5 g/kg. Skin over the anterior neck was opened and thecarotid artery and both jugular veins are cannulated with PE50 tubing toallow for blood pressure/heart rate monitoring and drug administration,respectively. The trachea was cannulated and the animal ventilated bypositive pressure, constant volume ventilation followed by paralysiswith succinylcholine (10 ug/kg/min) to paralyze the chest wallmusculature to remove the contribution of chest wall rigidity fromairway pressure measurements.

Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine fromnerve terminals that may interfere with vagal nerve stimulation. Bothvagus nerves were exposed and connected to electrodes to allow selectivestimuli of these nerves. Following 15 minutes of stabilization, baselinehemodynamic and airway pressure measurements were made before and afterthe administration of repetitive doses of i.v. histamine.

Following the establishment of a consistent response to i.v. histamine,vagal nerve stimulation was attempted at variations of 100 Hz, 0.5 msand 1.5 mA output current to identity parameters that attenuateresponses to i.v. histamine. Bronchoconstriction in response to i.v.histamine is known to be due to both direct airway smooth muscle effectsand due to stimulation of vagal nerves to release acetylcholine.

At the end of vagal nerve challenges atropine was administered i.v.before a subsequent dose of histamine to determine what percentage ofthe histamine-induced bronchoconstriction was vagal nerve induced. Thiswas considered a 100% response. Success of electrical interruption invagal nerve activity in attenuating histamine-inducedbronchoconstriction was compared to this maximum effect. Euthanasia wasaccomplished with intravenous potassium chloride.

In order to measure the bronchoconstriction, the airway pressure wasmeasured in two places. The blood pressure and heart rate were measuredto track the subjects' vital signs. In all the following graphs, the topline BP (red) shows blood pressure, second line AP1 shows airwaypressure, third line AP2 shows airway pressure on another sensor, thelast line HR is the heart rate derived from the pulses in the bloodpressure.

FIGS. 25 and 26 graphically illustrate exemplary experimental data fromthe experiment on another guinea pig. The graph shows the effects ofWernicke's 100 Hz, 1.5 mA, 0.5 mS waveform applied to both vagus nerveson the guinea pig. FIG. 25 illustrates two peaks in airway pressure (AP)from histamine alone with no treatment (the first two peaks) and a thirdpeak at the right of the graph after which Wernicke's signal was appliedat 1.2 mA. As shown, the results show no beneficial result on thehistamine-induced airway pressure increase or the blood pressure at 1.2mA. In FIG. 26, the first and third peaks in airway pressure (AP) arefrom histamine along with no treatment and the second peak illustratesairway pressure after Wernicke's signal was applied at 1.8 mA. As shown,the signal actually increased the histamine-induced airway pressure at2.8 mA, making it clinically worse. Thus, it is clear the Wernickesignals do not cause a decrease in airway pressure.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A method of treating a disease or disorder in a patient, the methodcomprising: positioning one more energy transmitters within a containercomprising electrically conducting fluid such that the energytransmitters are at least partially surrounded by the electricallyconductive fluid; positioning a surface of the container against anouter skin surface of a patient; and applying sufficient energy to theenergy transmitters to generate one or more electrical impulses at ornear a vagus nerve of the patient, wherein the electrical impulses aresufficient to stimulate activity of the vagus nerve to treat the diseaseor disorder.
 2. The method of claim 1 wherein the energy transmitterscomprise magnetic coils and the energy comprises a magnetic field. 3.The method of claim 2 wherein the electrically conductive fluid is anelectrically conductive gel.
 4. The method of claim 2 wherein theelectrically conductive fluid contains ferromagnetic particles.
 5. Themethod of claim 2 wherein the electrically conductive fluid comprises amagnetorheological fluid.
 6. The method of claim 2 wherein theelectrically conductive fluid is a combination of at least amagnetorheological fluid and a ferrofluid.
 7. The method of claim 1wherein the magnetic coils comprise toroids.
 8. The method of claim 1wherein the positioning step is carried out by contacting a handhelddevice comprising the container against a neck of the patient.
 9. Themethod of claim 1 wherein the energy transmitters are electrodes and theenergy comprises an electric current.
 10. The method of claim 1 whereinthe electrical impulses have a pulsed-on time from about 50 to about 500microseconds.
 11. The method of claim 1 wherein the electrical impulsesare sufficient to stimulate afferent fibers of the vagus nerve.
 12. Themethod of claim 1 wherein the disease or disorder comprisesbronchoconstriction.
 13. The method of claim 1 wherein the electricalimpulses have a frequency from about 1 to about 3000 Hz.
 14. The methodof claim 1 wherein the electrical impulses have a frequency from about15 to about 50 Hz.
 15. A device for treating a disease or disorder of apatient, the device comprising: a power source; a container coupled tothe power source and comprising an interior at least partially filledwith an electrically conductive fluid and one or more energytransmitters within the interior at least partially surrounded by theelectrically conductive fluid, the container further comprising acontact surface for contacting an outer skin surface of the patient; andwherein the power source supplies energy to the energy transmitters andthe energy is sufficient to generate one or more electrical impulses ata vagus nerve of the patient sufficient to treat the disease ordisorder.
 16. The device of claim 15 wherein the energy transmitterscomprise magnetic coils and the energy comprises a magnetic field. 17.The device of claim 16 wherein the electrically conductive fluidcontains ferromagnetic particles.
 18. The device of claim 16 wherein theelectrically conductive fluid comprises a magnetorheological fluid. 19.The device of claim 16 wherein the electrically conductive fluid is acombination of at least a magnetorheological fluid and a ferrofluid. 20.The device of claim 16 wherein the magnetic coils comprise toroids. 21.The device of claim 15 further comprising a handheld device configuredfor contacting a neck of the patient, wherein the power source and thecontainer are housed within the handheld device.
 22. The device of claim15 wherein the energy transmitters are electrodes and the energycomprises an electric current.
 23. The device of claim 15 wherein theelectrical impulses have a pulsed-on time from about 50 to about 500microseconds.
 24. The device of claim 15 wherein the disease or disordercomprises bronchoconstriction.
 25. The device of claim 15 wherein theelectrical impulses have a frequency from about 1 to about 3000 Hz. 26.The device of claim 15 wherein the electrical impulses have a frequencyfrom about 15 to about 35 Hz.